LOPD-3
CaseLOPD-3: 2 weeks diagnosis
HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.7%
GenotypingMethod: Newborn Screening Panels
Variant: NM_000152.4:c.2647-7G>A
ClinVar: 551106 https://www.ncbi.nlm.nih.gov/clinvar/variation/551106/
gnomAD: South Asian 3.266e-5, Overall 1.780e-5 http://gnomad.broadinstitute.org/variant/17-78092445-G-A
CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant
LOPD-7
CaseLOPD-7: 24 years diagnosis
CasePresentingHPOs: HP:0003236, HP:0012378, HP:0002910 (Increased serum CK, Fatigue, Elevated transaminases)
HPOsFreeText: GAA activity 4.0 (nmol · h−1 · mg−1), Mean percentage of normal 5.6%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)
ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease
LOPD-11
CaseLOPD-11: 8.3 years diagnosis
HPOsFreeText: GAA activity 2.0 (nmol · h−1 · mg−1), Mean percentage of normal 2.8%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Chromosomal code not provided
Variant2: NP_000143.2:p.Q743∗
ClinVar: N/A
gnomAD: N/A
CaseAddInfo: Late Onset Pompe Disease
PD/VOUS-5
CasePD/VOUS-5: 1.7 years diagnosis
HPOsFreeText: GAA activity 9.16 (nmol · h−1 · mg−1), Mean percentage of normal 12.9%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)
ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/
gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A
Variant3: NM_000152.4:c.1424C>T (p.Pro475Leu)
CAID: CA8815314 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.1424C%3ET
gnomAD: South Asian 1.307e-4, Overall 2.009e-5 http://gnomad.broadinstitute.org/variant/17-78083841-C-T
CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis
PD/VOUS-7
CasePD/VOUS-7: 3 weeks diagnosis
HPOsFreeText: GAA activity 3.43 (nmol · h−1 · mg−1), Mean percentage of normal 4.8%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)
ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/
gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A
Multiple interpretations of p.G615R possible
Variant3: NP_000143.2:p.G615R
CAID: PA113309 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NP_000143.2%3Ap.G615R
gnomAD: N/A
CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis
Supplement Table 1)
Patient13: 6yo
CasePresentingHPOs:
HPOsFreeText: rhGAA dosage = 20 EOW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 37mo at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.3:c.1781G>A
CAID: CA8815477, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8815477
gnomAD: 1.729e-05, http://exac.broadinstitute.org/variant/17-78086403-G-A
Supplement Table 1)
Patient5: 12yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA dosage = 20 EOW, ventilator dependent
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 6mo at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.3:c.2023_2025del
CAID: CA274244, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA274244
gnomAD: 2.105e-05, http://exac.broadinstitute.org/variant/17-78086806-CACA-C
Supplement Table 1)
Patient9: 2yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA dosage = 40 EOW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 14days old at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)
ClinVar: 371481, https://www.ncbi.nlm.nih.gov/clinvar/variation/371481/
gnomAD: 1.653e-05, http://exac.broadinstitute.org/variant/17-78093082-CTG-C
Supplement Table 1)
Patient8: 2yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA dosage = 40 EOW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 16 days old at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2:NM_000152.3:c.1197_1208del
CAID: CA658795246, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795246
gnomAD: n/a
4
Case#: Subject number 4(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 361 U/L (28-300 U/L is normal), AST: 66 U/L (24-72 U/L is normal), ALT: 52 U/L (17-63 U/L is normal), Hex4: 3.9 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)
glucosidase activity: GAA activity #1 was 1.24 micromole/L/h and GAA activity #2 (NBS) 0.67 in dried blood spots (>2.10 micromole/L/h is normal). 2.4 in confirmatory testing (>6.7 is normal).
Variant 1: NM_000152.5(GAA):c.-32-13T>G
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.-32-13T>G
Variant 2 ClinVarID: 4027
Variant 2 CAid: CA116606
Zygosity: homozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
27
Case#: Subject number 27(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 108 U/L (60-305 U/L is normal), AST: 32 U/L (22-71 U/L is normal), ALT: 29 U/L (7-50 U/L is normal), Hex4: 3.3 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 35.7 pg/mL (0.0–100.0 pg/mL is normal)
glucosidase activity: GAA activity #1 (NBS) is 1.1 micromole/L/h and GAA activity #2 (NBS) 0.42 in dried blood spots (>2.10 micromole/L/h is normal). 2.40 in confirmatory testing (>3.88 is normal).
Variant 1: NM_000152.5(GAA):c.1441T>C
Variant 1 ClinVarID: 189007
Variant 1 CAid: CA274247
Variant 2: NM_000152.5(GAA):c.2238G>C
Variant 2 ClinVarID: 265160
Variant 2 CAid: CA8815665
Variant 3: NM_000152.5(GAA):c.2065G>A
Variant 3 ClinVarID: 4030
Variant 3 CAid: CA116612
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
15
Case#: Subject number 15(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 68 U/L (60-305 U/L is normal), AST: 49 U/L (20-64 U/L is normal), ALT: 27 U/L (12-42 U/L is normal), Hex4: 2.8 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)
glucosidase activity: GAA activity #1 was 1.11 micromole/L/h and GAA activity #2 (NBS) 0.5 in dried blood spots (>2.10 micromole/L/h is normal). 1.60 in confirmatory testing (>3.88 is normal).
Variant 1: NM_000152.5(GAA):c.2238G>C
Variant 1 ClinVarID: 265160
Variant 1 CAid: CA8815665
Variant 2: NM_000152.5(GAA):c.-32-13T>G
Variant 2 ClinVarID: 4027
Variant 2 CAid: CA116606
Variant 3: NM_000152.5(GAA):c.2065G>A
Variant 3 ClinVarID: 4030
Variant 3 CAid: CA116612
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
24
Case#: Subject number 24(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 197 U/L (60-305 U/L is normal)
glucosidase activity: GAA activity #2 (NBS) 0.43 in dried blood spots (>2.10 micromole/L/h is normal).
Variant 1: NM_000152.5(GAA):c.1856G>A
Variant 1 ClinVarID: 370146
Variant 1 CAid: CA8815500
Variant 2: NM_000152.5(GAA):c.2238G>C
Variant 2 ClinVarID: 265160
Variant 2 CAid: CA8815665
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
21
Case#: Subject number 21(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 155 U/L (60-305 U/L is normal), AST: 71 U/L (22-71 U/L is normal), ALT: 60 U/L (7-50 U/L is normal), Hex4 12.6 mmol/mol Creatine (≤20 is normal)
glucosidase activity: GAA activity #1 was 1.77 micromole/L/h and GAA activity #2 (NBS) 0.84 in dried blood spots (>2.10 micromole/L/h is normal).
Variant 1: NM_000152.5(GAA):c.-32-13T>G
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.-32-13T>G
Variant 2 ClinVarID: 4027
Variant 2 CAid: CA116606
Zygosity: homozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
19
Case#: Subject number 19(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 510 U/L (60-305 U/L is normal), AST: 158 U/L (22-71 U/L is normal), ALT: 39 U/L (7-50 U/L is normal), Hex4: 8.1 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP <10.0 pg/mL (0.0–100.0 pg/mL is normal)
glucosidase activity: GAA activity #1 was 1.07 micromole/L/h and GAA activity #2 (NBS) 0.38 in dried blood spots (>2.10 micromole/L/h is normal). 1.10 in confirmatory testing (>3.88 is normal).
Variant 1: NM_000152.5(GAA):c.456_458insGA
Variant 1 ClinVarID: ?
Variant 1 CAid: ?
Variant 2: NM_000152.5(GAA):c.-32-13T>G
Variant 2 ClinVarID: 4027
Variant 2 CAid: CA116606
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
18
Case#: Subject number 18(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 542 U/L (60-305 U/L is normal), AST: 152 U/L (22-71 U/L is normal), ALT: 55 U/L (7-50 U/L is normal), Hex4: 7.6 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 16.5 pg/mL (0.0–100.0 pg/mL is normal)
glucosidase activity: GAA activity #1 was 0.7 micromole/L/h and GAA activity #2 (NBS) 0.34 in dried blood spots (>2.10 micromole/L/h is normal). 1.40 in confirmatory testing (>3.88 is normal).
Variant 1: NM_000152.5(GAA):c.-32-13T>G
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.2560C>T
Variant 2 ClinVarID: 4034
Variant 2 CAid: CA340130
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
9
Case#: Subject number 9(L)
DiseaseAssertion: Late Onset Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CK testing: 145 U/L (60-305 U/L is normal), AST: 72 U/L (22-71 U/L is normal), ALT: 43 U/L (7-50 U/L is normal), Hex4: 5.3 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 13.0 pg/mL (0.0–100.0 pg/mL is normal)
glucosidase activity: GAA activity #1 was 0.97 micromole/L/h and GAA activity #2 (NBS) 0.33 in dried blood spots (>2.10 micromole/L/h is normal). 0.93 in confirmatory testing (>3.88 is normal).
Variant 1: NM_000152.5(GAA):c.2238G>C
Variant 1 ClinVarID: 265160
Variant 1 CAid: CA8815665
Variant 2: NM_000152.5(GAA):c.2281delGinsAT
Variant 2 ClinVarID: 370993
Variant 2 CAid: CA16041905
Variant 3: NM_000152.5(GAA):c.2065G>A
Variant 3 ClinVarID: 4030
Variant 3 CAid: CA116612
Zygosity: compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
These results were confirmed in a fibroblast cell line from patient 2
Patient2: concentration-dependent effects of AONs 3 and 4 confirmed in a fibroblast cell line from this patient, this concluded that these AONs show in vitro activities sufficient to elevate canonical GAA pre-mRNA splicing and thus enzymatic activity
CasePresentingHPOs:
HPOsFreeText:
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: n/a
CaseGenotypingMethod: n/a
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.3:c.923A>C
CAID: CA401364056, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401364056
gnomAD: n/a
To validate the U7 snRNA vector, a control experiment was performed on primary fibroblasts derived from a patient with adult Pompe disease (patient 1), who carried the IVS1 variant on one allele and the c.525delT on the second allele.
Patient1: control experiment performed on patient's primary fibroblasts to validate U7 snRNA vector, screen showed multiple U7 snRNA-based AONs that modulate inclusion of exon 2 in GAA mRNA
CasePresentingHPOs:
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: n/a
CaseGenotypingMethod: n/a
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)
ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C
4
Case4: Male, 0.8 yr onset, 2 yr diagnosis, 2.4 yr report
HPOsFreeText: 1353 CK U/l, 13 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, no respiratory support
13
Case13: Male, 5 yr onset, 2 yr diagnosis, 7.6 yr report
HPOsFreeText: Respiratory support at night, FVC z-score sitting -1.77 (78% pred), FVC z-score supine -1.72 (79% pred), 100% MRC Scale, 436 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used
16
Case#: Subject number 16, male, 22 years (baseline visit)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)
CaseHPOFreeText:
CaseNotHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)
CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit
CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"
PreviouslyPublished: N/A
6
Case#: Subject number 6, female, 36 years (diagnosis), 51 years (baseline visit), 47 years (ERT)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001324 (Muscle Weakness)
CaseHPOFreeText:
CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)
CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit
CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"
PreviouslyPublished: N/A
28
Case#: Subject number 28, male, 20 years (diagnosis), 43 years (baseline visit), 43 (ERT)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001324 (Muscle Weakness)
CaseHPOFreeText:
CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)
CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit
CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"
PreviouslyPublished: N/A
23
Case#: Subject number 23, male, 2 years (diagnosis), 8 years (baseline visit)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)
CaseHPOFreeText:
CaseNotHPOs: HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)
CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit
CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"
PreviouslyPublished: N/A
33
Case#: Subject number 33, female, 16 years (diagnosis), 20 years (baseline visit)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)
CaseHPOFreeText:
CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness)
CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit
CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"
PreviouslyPublished: N/A
PD02
Patient2: Female, northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
Variant2: NM_000152.3:c.859-2A>T
CAID: CA401363789, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401363789
gnomAD: n/a
PD09
Patient9: Female, Northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.796C>T (p.Pro266Ser)
ClinVar: 556117, https://www.ncbi.nlm.nih.gov/clinvar/variation/556117/
gnomAD: n/a
Variant2: NM_000152.3:c.1602_1605delinsAGG
CAID: CA913184733, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184733
gnomAD: n/a
PD01
Patient1: Female, northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)
ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/
PD21
Patient21: Female, Northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)
ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/
gnomAD: n/a
Variant2: NM_000152.3:c.1844G>T
CAID: CA401369601, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369601
gnomAD: n/a
PD24
Patient24: Female, Northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: c.1151 + 2T > G no ClinVar or CAID, intronic position inside exon
Variant2: NM_000152.3:c.1562A>T
CAID: CA401367205, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401367205
gnomAD: 0.000003980, http://gnomad.broadinstitute.org/variant/17-78084750-A-T
6
Case#: Patient 6, Gender N/A, Onset at 5-6 months. Death around 2 years old, Southeast Asian
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: P:0001639. HP:0005165, HP:0001270, HP:0011968
(Dyspnea, Shortened PR interval, Motor delay, Feeding difficulties,
CaseHPOFreeText: FTT, BVH, Severe MR)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: GAA activity in leukocytes was 0.43% of normal control value.
PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions
Variant: NM_000152.5(GAA):c.781G>A (p.Ala261Thr)
ClinVar: 456438
CAID: CA8815016
gnomAD: Highest population MAF = 0.00009799 (South Asian)
ParentalGenotype: Father and Mother were carriers of the variant c.781G>A (p.Ala261Thr)
PreviouslyPublished: N/A
10
Case#: Patient 10, Gender N/A, Onset at 1-2 months. Death at 10 months, Southeast Asian
DiseaseAssertion:Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639. HP:0005165, HP:0002100
(Dyspnea, Shortened PR interval, Recurrent aspiration pneumonia)
CaseHPOFreeText: BVH, SDD
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting GAA enzyme activity is not available.
PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions
Variant: NM_000152.5(GAA):c.876C>G (p.Tyr292Ter)
ClinVar: 637958
CAID: CA500127534
gnomAD: N/A
ParentalGenotype: Both parents are carriers of the variant c.876C>G (p.Tyr292Ter)
PreviouslyPublished: N/A
Patient 1 was a 22-year old Caucasian female
Patient1: female, 22 yo, Caucasian
CasePresentingHPOs: HP:0003710, HP:0003326, HP:0040081, HP:0045040, HP:0002910
HPOsFreeText: CK = 571 U/l, LDH = 301 U/l, ASAT = 85 U/l, ALAT = 84 U/l, GAA activity = 0.31nmol/spot x21hrs, small droplet lipid deposits in the muscle fibres of vastus lateralis
CaseNotHPOs: HP:0003457, HP:0009051, HP:0001639, HP:0002111, HP:0002093
NotHPOsFreeText: MRI of thigh muscles showed no abnormalities, no changes in the PAS positive inclusions
CaseAddInfo: 14yo at symptom onset, no family history of neuromuscular disease
CasePreviousTesting: EMG, MRI, muscle biopsy of mm. vastus lateralis, hematoxylin and eosin stain, Peri acid-Schiff reaction, Acid phosphatase staining,transthoracic echocardiogram, respiratory function test
CaseGenotypingMethod: Sanger Sequencing
Variant: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
2
Case#: P 2, Female, 4.7 months old when started ERT (113.7 months old at publication date), ethnicity unknown
DiseaseAssertion: Pompe disease
FamilyInfo: Table 1 includes parental genotype
CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090
(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Pneumonia)
CaseHPOFreeText: Aspiration pneumonia was a complication during ERT.
Patient requires tube feeding.
Patient's best and current motor status is being able to sit.
CaseNotHPOs: N/A
CaseNotHPOFreeText: Patient has not required ventilation
CasePreviousTesting: CRIM status is positive in patient
Antibody titer is 1:1.200
Variant 1: NM_000152.5(GAA):c.1799G>A (p.Arg600His)
ClinVar: 370130
CAID: CA8815482
gnomAD: Highest population MAF= 0.00003267 in South Asians
Variant 2: c.1859G>A
ClinVar: N/A
CAID: N/A
gnomAD: N/A
ParentalGenotype: Mother is the carrier of the c.1799G>A (p.Arg600His) Variant
Father is the carrier of the c.1859G>A variant
PreviouslyPublished: N/A
14
Case#: P 14, Male, 1.5 months old when started ERT (Died at 41.8 months old), German
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090
(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Pneumonia)
CaseHPOFreeText: Pneumonia and deterioration were complications during ERT
Required ventilation
CaseNotHPOs: N/A
CaseNotHPOFreeText: Did not required tube feeding
CasePreviousTesting: CRIM Status and Antibody titer are unknown
Variant: NM_000152.5(GAA):c.1978C>T (p.Arg660Cys)
ClinVar:<br /> 558604
CAID: CA8815561
gnomAD: MAF=0.00005554 in East Asian
ParentalGenotype: Both the paternal and maternal allele carry the variant c.1978C>T (p.Arg660Cys)
PreviouslyPublished: N/A
5
Case#: P 5, Male, 0.9 months old when started ERT (76.9 months old at publication date), Ethnicity unknown
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0006532
(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Recurrent pneumonia)
CaseHPOFreeText: Recurrent pneumonia was a complication during ERT.
AR III
Patient requires tube feeding and is ventilated
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: CRIM status is unknown
Antibody titer is 1:12,000
Variant: NM_000152.5(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595
CAID: CA8815829
gnomAD: Highest population MAF= 0.0002719 (East asian)
ParentalGenotype: Both the paternal and maternal allele carry the c.2662G>T (p.Glu888Ter) Variant
PreviouslyPublished: N/A
3
Case3: Female, Swedish, 64 years report, 48 years onset
CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)
HPOsFreeText: 6-min walk test achieved 369 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 2.8/2.7 (L), On the medications Zopiklon and Ketoprofen
NotHPOsFreetext: Not on ERT
GroupGenotypingMethod: Mutation Analysis on the GAA Gene
Variant1: NM_000152.4:c.2560C>T (p.Arg854Ter)
ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/
gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T
Variant2: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
CaseAddInfo: Late Onset Pompe Disease
6
Case6: Female, French, 26 years report, 21 years onset
CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)
HPOsFreeText: 6-min walk test achieved 496 m, MRC score is 3/5 (thigh/calf), Forced vital capacity sitting/supine is 2.2/1.9 (L), Has started ERT,On the medication Perindopril
GroupGenotypingMethod: Mutation Analysis on the GAA Gene
Variant1: NM_000152.4:c.-32-13T>A
CAID: CA913184742 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184742
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.525delT (p.Glu176Argfs)
ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
CaseAddInfo: Late Onset Pompe Disease
Ten patients received concomitant immunomodulation (detailed in Supplementary Table S4); six were genotype-predicted as CRIM-negative, three were CRIM-positive, and one lacked genotype data.
Patient 5
Variant1: NM_000152.3:c.1396del
CAID: CA658795256, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795256
gnomAD: n/a
Variant2: NM_000152.3:c.1705dup
CAID: CA658795264, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1705dup
gnomAD: n/a
3.1 Description of the study population
Patient5: IOPD Group, 12days old
CasePresentingHPOs:
HPOsFreeText: LDH = 464 U/L, CK = 380 U/L, ALT = 58 U/L, AST = 100 U/L, Mann-Whitney Test = 2
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A
3.1 Description of the study population
Patient3: IOPD Group, 11days old
CasePresentingHPOs:
HPOsFreeText: LDH = 664 U/L, CK = 809 U/L, ALT = 48 U/L, AST = 117 U/L, Mann-Whitney Test = 3
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A
3.1 Description of the study population
Patient9: IOPD Group, 14days old
CasePresentingHPOs:
HPOsFreeText: LDH = 597 U/L, CK = 998 U/L, ALT = 43 U/L, AST = 102 U/L, Mann-Whitney Test = 3
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A
T
CaseA1: 26 years onset
CaseAddInfo: Late-Onset Pompe Disease, Sibling of A2
#22
Case22: Male, 16 years onset, 41 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
#13
Case13: Male, 9 years onset, 19 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
4
Case#: Patient 4
DiseaseAssertion: Pompe Disease
FamilyInfo: None given
CasePresentingHPOs: None
CaseHPOFreeText: None
CaseNotHPOs: None
CaseNotHPOFreeText: None
CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine
Glucosidase activity: 0.0 nmol 5MU/hr/mL
Variant 1: NM_000152.5:c.596A>G
Variant 1 ClinVarID: 92486
Variant 1 CAid: CA145785
Variant 2: NM_000152.5:c.668G>A
Variant 2 ClinVarID: 92488
Variant 2 CAid: CA145791
ParentalGenotype: Not provided
5
Case#: Patient 5
DiseaseAssertion: Pompe Disease
FamilyInfo: None given
CasePresentingHPOs: None
CaseHPOFreeText: None
CaseNotHPOs: None
CaseNotHPOFreeText: None
CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine
Glucosidase activity: 0.0 nmol 5MU/hr/mL
Variant 1: NM_000152.5:c.2560C>T
Variant 1 ClinVarID: 4034
Variant 1 CAid: CA340130
Variant 2: NM_000152.5:c.2446G>A
Variant 2 ClinVarID: 92477
Variant 2 CAid: CA145772
ParentalGenotype: Not provided
7
Case#: Patient 7
DiseaseAssertion: Pompe Disease
FamilyInfo: None given
CasePresentingHPOs: None
CaseHPOFreeText: None
CaseNotHPOs: None
CaseNotHPOFreeText: None
CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine
Glucosidase activity: 0.05 nmol 5MU/hr/mL
Variant 1: NM_000152.5:c.2560C>T
Variant 1 ClinVarID: 4034
Variant 1 CAid: CA340130
Variant 2: NM_000152.5:c.596A>G
Variant 2 ClinVarID: 92486
Variant 2 CAid: CA145785
Variant 3: NM_000152.5:c.668G>A
Variant 3 ClinVarID: 92488
Variant 3 CAid: CA145791
ParentalGenotype: Not provided
9
Patient9: Male, <1 year onset
CaseAddInfo: LOPD
7
Patient7: Female, 1 year onset
CasePresentingHPOs: HP:0002240 (Hepatomegaly)
HPOsFreeText: GAA activity 1% from leukocyte
CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640 (Respiratory distress, Muscle weakness, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
3
Patient3: Female, 6 years report, birth onset
CasePresentingHPOs: HP:0001640, HP:0002240, HP:0001324 (Cardiomegaly, Hepatomegaly, Muscle weakness)
HPOsFreeText: GAA activity 2.1% from leukocyte
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: IOPD
Case 2A 50-day-old male infant was diagnosed with IOPD (Table 1)
Case#: Case 2, male, 50 days old when diagnosed, ethnicity unknown
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001638, HP:0001252, HP:0000282 (cardiomyopathy, muscular hypotonia, facial edema)
CaseHPOFreeText:(Associated to Pompe disease) increased serum CK.
CaseHPOFreeText: (Infussion associated reactions) Generalized rash, cough and bronchospasm
CaseNotHPOs: N/A
CaseNotHPOFreeText: Infusion associated reactions are not associated with an IgE mediated mechanism.
CasePreviousTesting: See Table 1 for reports on GAA metabolic activity.
GAA activity in dried blood spots is 0 μmol/l/h with a reference range of 1.86–21.9 μmol/l/h
GAA activity on lymphocytes is 0.5 nmol 4 Mu/mg prot/h with a reference range of 21.4 ± 6.2 nmol 4 Mu/mg prot/h
Variant: c1124G>T (p.R375L)
ClinVar: N/A
CAID: N/A
gnomAD: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
35
Patient35: male, Caucasian
CasePresentingHPOs: HP:0003676, HP:0003236, HP:0003325, HP:0008994, HP:0003458, HP:0003560, HP:0030121
HPOsFreeText: CK < 10x increase, difficulty ascending stairs, inability to stand without aid, treated with ERT
CaseNotHPOs: HP:0002093
CaseAddInfo: onset as young adult. Older sister also affected with onset at 21 yo. She now exhibits scoliosis, fatigability, paraspinal muscle atrophy, proximal upper limp atrophy, and weakness. Calpain deficiency detected via immunoblot could be connected to CAPN3 variants (p.Gly333Asp [c.998G > A] and p.Ala726Ser [c.2176G > T]).
CasePreviousTesting: same as group, EMG, muscle biopsy, immunoblot analysis
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.569G>A (p.Arg190His)
ClinVar: 188809, https://www.ncbi.nlm.nih.gov/clinvar/variation/188809/
gnomAD: 8.276e-06, http://exac.broadinstitute.org/variant/17-78079570-G-A
Variant2: NM_000152.3:c.2020C>G
CAID: CA401370092, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370092
gnomAD: n/a
CaseOPOPD-11: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.98 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.701C>T (p.Thr234Met)
ClinVar: CA8814994 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.701C%3ET
gnomAD: South Asian 3.266e-5, Overall 1.196e-5 http://gnomad.broadinstitute.org/variant/17-78081364-C-T
Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation
CaseLP-1: Female, Taiwan, Birth diagnosis
HPOsFreeText: 4MU enzyme activity at 0.44, MS/MS ennzyme activity at 0.08
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.3:c.424_440del (p.Ser142Leufs*29)
CAID: CA658795228 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.424_440del17
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.1958C>A (p.Thr653Asn)
CAID: CA8815557 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1958C%3EA
gnomAD: East Asian 2.548e-4, Overall 1.825e-5 http://gnomad.broadinstitute.org/variant/17-78086744-C-A
CaseAddInfo: Suspected Late Onset Pompe Disease
CaseIP2-2: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.09 umol/hr/L, Serum CK at 458 U/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.872T>C (p.Leu291Pro)
CAID: CA401363854 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.872T%3EC
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)
ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A
Variant3: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 1 and 2 are in trans, also that Variant 3 is in cis with only one of them
CasePDC-1: Female, Taiwan, Birth diagnosis
HPOsFreeText: 4MU enzyme activity at 1.15, MS/MS ennzyme activity at 1.2
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
CaseAddInfo: Patient is either a carrier or has a pseudodeficency allele, Second allele is wildtype
CaseLP-2: Female, Taiwan, Birth diagnosis
HPOsFreeText: 4MU enzyme activity at 0.85, MS/MS ennzyme activity at 0.42
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.671G>A (p.Arg224Gln)
CAID: CA8814958 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.671G%3EA
gnomAD: African 8.060e-5, Overall 2.549e-5 http://gnomad.broadinstitute.org/variant/17-78079672-G-A
Variant2: NM_000152.4:c.752C>T (p.Ser251Leu)
ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/
gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T
Variant3: NM_000152.4:c.761C>T (p.Ser254Leu)
ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/
gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T
CaseAddInfo: Suspected Late Onset Pompe Disease, Nomenclature indicates Variants 2 and 3 are in cis
CaseOPOPD-5: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.97 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.503G>C (p.Arg168Pro)
CAID: CA401361673 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.503G%3EC
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation
10
Case#: Subject number 10, male, 70 years (report), 58 years (onset), 65 years (diagnosis)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0000365 (hearing loss)
CaseHPOFreeText: on BiPAP, ambulatory, assistive device (walking stick occasionally)
CaseNotHPOs: HP:0000360, HP:0000821, HP:0002650, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0001638 (tinnitus, hypothyroidism, scoliosis, aneurysm, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, cardiomyopathy)
CaseNotHPOFreeText: no infusion reaction, no tracheostomy
CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy
Variant 1: NM_000152.5(GAA):c.-32-13T>G (p.Tyr766Ser)
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.2655_2656delCG (p.Val886GlufsTer2)
Variant 2 ClinVarID: 597005
Variant 2 CAid: CA913191011
Zygosity: Compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
18
Case#: Subject number 18, male, 65 years (report), 40 years (onset), 62 years (diagnosis)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0000365 (hearing loss), HP:0000939 (osteoporosis), HP:0001638 (cardiomyopathy)
CaseHPOFreeText: ambulatory, on BiPAP
CaseNotHPOs: HP:0000360, HP:0000821, HP:0002650, HP:0002617, HP:0009830, HP:0100647, HP:0010788 (tinnitus, hypothyroidism, scoliosis, aneurysm, peripheral neuropathy, Graves disease, Testicular cancer)
CaseNotHPOFreeText: no tracheostomy, no infusion reaction
CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy
Variant 1: NM_000152.5(GAA):c.-32-13T>G (p.Tyr766Ser)
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.1051delG
Variant 2 ClinVarID: 188841
Variant 2 CAid: CA274024
Zygosity: Compound heterozygous
ParentalGenotype: N/A
6
Case#: Subject number 6, female, 57 years (report), 20s years (onset), 31 years (diagnosis)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0002650 (scoliosis)
CaseHPOFreeText: on BiPAP, ambulatory, assistive device (walker)
CaseNotHPOs: HP:0000360, HP:0000365, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0000821, HP:0001638 (tinnitus, hearing loss, aneurysm, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, hypothyroidism, cardiomyopathy)
CaseNotHPOFreeText: No infusion reaction, no tracheostomy
CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy
Variant 1: NM_000152.5(GAA):c.-32-13T>G (p.Tyr766Ser)
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.925G>A (p.Gly309Arg)
Variant 2 ClinVarID: 188797
Variant 2 CAid: CA273972
Zygosity: Compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
2
Case#: Subject number 2, male, 48 years (report), 39 years (onset), 43 years (diagnosis)
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0002617 (aneurysm)
CaseHPOFreeText: on BiPap, ambulatory
CaseNotHPOs: HP:0000365, HP:0000360, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0000821, HP:0002650, HP:0001638 (hearing loss, tinnitus, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, hypothyroidism, scoliosis, cardiomyopathy)
CaseNotHPOFreeText: No infusion reaction, no tracheostomy
CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy
20 mg/kg (N = 16)
Case16HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.1 umol/h/L, GAA activity at 33% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.722_723delTT (p.Phe241Cysfs*?)
CAID: CA658795235 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.722_723delTT
gnomAD: Not in gnomAD
CaseAddInfo:
20 mg/kg (N = 16)
Case15HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 8.3 pmol/spot/hr, GAA activity at 35% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.2482_2646del165 (p.Gly828_Asn882del) (Exon 18 del)
ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/
gnomAD: Not in gnomAD
CaseAddInfo:
20 mg/kg (N = 16)
Case21HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.8 U/g, GAA activity at 8.9% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G
No information given to identify where the variant is
Variant2: NM_000152.4: IVS15+2T>A
ClinVar:
gnomAD:
CaseAddInfo:
20 mg/kg (N = 16)
Case12HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 4 nmol/punch/hr, GAA activity at 15% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.546+1G>T
CAID: CA401361913 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B1G%3ET
gnomAD: Not in gnomAD
CaseAddInfo:
#10
Case#: Subject number 10, male, 46 years (report)
DiseaseAssertion: Pompe disease
FamilyInfo: No known family member with PD
CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia)
CaseHPOFreeText:
CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress), HP:0002153 (hyperkalemia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002094 (dyspnoea)
CaseNotHPOFreeText: no biopsy, not asymptomatic
CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."
glucosidase activity: GAA activity was 0.36 mol/Lh in dried blood spots (normal range >0.75).
Variant 1: NM_000152.5(GAA):c.-32-13T>C
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.236_246delCCACACAGTGC (p.Pro79ArgfsTer13)
Variant 2 ClinVarID: 371302
Variant 2 CAid: CA16041880
Zygosity: Compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
#8
Case#: Subject number 8, female, 32 years (report)
DiseaseAssertion: Pompe disease
FamilyInfo: No known family member with PD
CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness)
CaseHPOFreeText:
CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)
CaseNotHPOFreeText: no biopsy, not asymptomatic
CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."
glucosidase activity: GAA activity was 0.3 mol/Lh in dried blood spots (normal range >0.75).
Variant 1: NM_000152.5(GAA):c.-32-13T>C
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.925G>A (p.Gly309Arg)
Variant 2 ClinVarID: 188797
Variant 2 CAid: CA273972
Zygosity: Compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
#13
Case#: Subject number 13, female, 57 years (report)
DiseaseAssertion: Pompe disease
FamilyInfo: No known family member with PD
CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea)
CaseHPOFreeText:
CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress)
CaseNotHPOFreeText: no biopsy, not asymptomatic
CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."
glucosidase activity: GAA activity was 0.37 mol/Lh in dried blood spots (normal range >0.75).
Variant 1: NM_000152.5(GAA):c.-32-13T>C
Variant 1 ClinVarID: 4027
Variant 1 CAid: CA116606
Variant 2: NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)
Variant 2 ClinVarID: 188484
Variant 2 CAid: CA198797
Zygosity: Compound heterozygous
ParentalGenotype: N/A
PreviouslyPublished: N/A
93
Case#: 93, gender N/A, 6months old when diagnosed, Asian
DiseaseAssertion: Pompe disease
FamilyInfo: Both parents were carriers of mutations in the GAA gene. The patient inherited the mutations.
CasePresentingHPOs: N/A
CaseHPOFreeText: Symptoms were noted at the age of 2.7 months old
CaseNotHPOs: N/A
CaseNotHPOFreeText: The patient showed no symptoms but LOPD was diagnosed based on the predicted impact of the variants by PolyPhen-2
CasePreviousTesting: The GAA gene was sequenced using NGS and resequenced for confirmation using Sanger.
Dried Blood spot test found an GAA activity of 0.25 pmol/h/disk with a reference value of 6.5 pmol/h/disk
Variant1: NM_000152.5(GAA):c.317G>A (p.Arg106His)
ClinVar: 286481
CAID: CA8814849
gnomAD: MAF=0.0001094 in East Asian
Variant2: (COMBINATION OF MUTATIONS IN THIS ALLELE, DOUBT HERE)
Variant2.1: NM_000152.5(GAA):c.752C>T (p.Ser251Leu)
ClinVar: 346310
CAID: CA8815007
gnomAD: Highest population MAF = 0.002234 (East Asian)
Variant2.2: NM_000152.5(GAA):c.761C>T (p.Ser254Leu)
ClinVar: 330447
CAID: CA8815009
gnomAD: Highest population MAF= 0.002235 (East Asians)
ParentalGenotype: Father is heterozygous for c.317G>A (p.Arg106His).
Mother carries both mutations of c.[752C>T,761C>T].
PreviouslyPublished:N/A
Case33: Female, 79 years report
HPOsFreeText: ERT not started, 6 Minute Walking Test at 312 meters, Forced Vital Capacity at 113%
GenotypingMethod: GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.1560C>G (p.Asn520Lys)
CAID: CA401367200 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1560C%3EG
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease
Case16: Female, 61 years report
HPOsFreeText: 7 years of ERT completed, 6 Minute Walking Test at 392 meters, Forced Vital Capacity at 52%
GenotypingMethod: GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.693-1G>C
CAID: CA401362948 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.693-1G%3EC
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease
20
Case20: Male, 8 years onset, 11 years diagnosis, 11 years report
CasePresentingHPOs: HP:0003236 (Increased serum CK)
HPOsFreeText: Asymptomatic hyperCKemia
CaseAddInfo: Late-Onset Pompe Disease
12
Case12: Female, Unknown years onset, Unknown years diagnosis, 50 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)
CaseAddInfo: Late-Onset Pompe Disease
PD02
Patient2: Female, northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
Variant2: NM_000152.3:c.859-2A>T
CAID: CA401363789, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401363789
gnomAD: n/a
c.2560C > T(p.Arg854*)
Case12
HPOsFreeText: See Group Phenotypes
CasePreviousTesting: Sanger sequencing
CaseMethod1: Sanger sequencing and PCR Amplification
CaseMethod2: Whole Exome Sequencing (WES)
CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.
Variant1: NM_000152.4:c.2560C>T (p.Arg854*)
ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/
gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T
Variant2: NM_000152.4:c.1654delC (p.Leu552Serfs*26)
CAID: CA658795262 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1654delC
gnomAD: Not in gnomAD
CaseAddInfo: Infantile Onset Pompe Disease
c.1798C > T(p.Arg600Cys)
Case65
HPOsFreeText: See Group Phenotypes
CasePreviousTesting: Sanger sequencing
CaseMethod1: Sanger sequencing and PCR Amplification
CaseMethod2: Whole Exome Sequencing (WES)
CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.
Variant1: NM_000152.4:c.1798C>T (p.Arg600Cys)
CAID: CA8815481 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1798C%3ET
gnomAD: South Asian 3.267e-5, Overall 4.025e-6 http://gnomad.broadinstitute.org/variant/17-78086420-C-T
Variant2: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
CaseAddInfo: Adult Late Onset Pompe Disease
c.525delT(p.Glu176Argfs*45)
Case51
HPOsFreeText: See Group Phenotypes
CasePreviousTesting: Sanger sequencing
CaseMethod1: Sanger sequencing and PCR Amplification
CaseMethod2: Whole Exome Sequencing (WES)
CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.
Variant1: NM_000152.4:c.525delT (p.Glu176Argfs*45)
ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
Variant2: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
CaseAddInfo: Infantile Onset Pompe Disease
10
Case10: Male, 50 years onset, 52 years diagnosis, Italy
HPOsFreeText: See Group Phenotypes, ERT started at 53, GAA Activity at ~13 pmol/min/mg before ERT and ~15 after
GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.784G>A (p.Glu262Lys)
ClinVar: 188806 https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/
gnomAD: East Asian 5.016e-5, Overall 1.417e-5 http://gnomad.broadinstitute.org/variant/17-78081447-G-A
CaseAddInfo: Late Onset Pompe Disease
5
Case5: Male, 65 years onset, 72 years diagnosis, Italy
HPOsFreeText: See Group Phenotypes, ERT started at 72, GAA Activity at ~6 pmol/min/mg before ERT and ~10.5 after
GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.525delT (p.Glu176Argfs*45)
ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
CaseAddInfo: Late Onset Pompe Disease
16
Patient16: Male
CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522
HPOsFreeText: ERT dosage = 29mg/kg/2w
CaseNotHPOs:
NotHPOsFreeText: No HCM reversal
CaseAddInfo: Symptom onset at 2days, diagnosis and ERT at 10mo, ERT lasted for 6mo, required ventilation at 11mo, died at 16mo
CasePMIDs: 14695532
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.3:c.1431del
CAID: CA502178465, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA502178465
gnomAD: n/a
9
Patient9: Male
CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522
HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM negative
CaseNotHPOs:
NotHPOsFreeText: no HCM reversal
CaseAddInfo: Symptom onset at 2mo, diagnosis at 4mo, ERT at 4.5mo, ERT lasted for 4mo, ventilation required at 7mo, died at 10mo
CasePMIDs: 22252923, 27629047
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.3:c.1657C>T
CAID: CA401368835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1657C%3ET
gnomAD: n/a
Patient 3
Case#: Patient 3, female, symptoms began at birth, diagnosed at 5 weeks
DiseaseAssertion: Pompe Disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639, HP:0003712 (hypertrophic cardiomyopathy, hypertrophy of calves)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: <1% normal GAA expression in fibroblast; after ERT treatment had 100% enzyme activity in cell lysates; unclear how patient was diagnosed
Variant 1: NM_000152.5:c.525delT
Variant 1 ClinVarID: 4033
Variant 1 CAid: CA220406
Variant 2: NM_000152.5:c.525delT
Variant 2 ClinVarID: 4033
Variant 2 CAid: CA220406
ParentalGenotype: Not provided
10
Patient10: 50yo
CasePresentingHPOs: HP:0003325, HP:0004944, HP:0020038
HPOsFreeText: GAA = 3.6%, BMI = 22.4, MCA M1 4mm aneurysm, normal CT
CaseNotHPOs:
NotHPOsFreeText: No cardiovascular risk factor
CaseAddInfo: 13yr disease duration, variants in cis
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4(GAA):c.1551+1G>C
ClinVar: 554983, https://www.ncbi.nlm.nih.gov/clinvar/variation/554983/
gnomAD: n/a
4
Case4: Female, 16 years diagnosis, 13 years onset
CasePresentingHPOs: HP:0009073, HP:0003198, HP:0003236, HP:0003327, HP:0008994 (Progressive proximal muscle weakness, Myopathy, Increased serum CK, Axial muscle weakness, Proximal muscle weakness in lower limbs)
HPOsFreeText: Electromyography showed myogenic damage, Vacuolar myopathy, Serum CK is 1652.0 U/L
P7a
Patient7: Male, 59yo
CasePresentingHPOs: HP:0000822, HP:0000819, HP:0003077, HP:0001513
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 5yr follow-up MRI, 14yr disease duration, ERT lasted for 135mo
CasePMIDs: PMID: 25614309
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4(GAA):c.307T>G (p.Cys103Gly)
ClinVar: 92483, https://www.ncbi.nlm.nih.gov/clinvar/variation/92483/
gnomAD: n/a
P1a
Patient1: Female 26yo
CasePresentingHPOs: HP:0003077
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 5year follow-up MRI, 15yr disease duration, ERT lasted for 67mo
CasePMIDs: PMID: 25614309
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: IVS9 G > C no ClinVar or CAID
P12
Patient12: Female, 66yo
CasePresentingHPOs: HP:0003077, HP:0000822
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 7yr disease duration, ERT lasted 33mo
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)
ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
3
Case#: Patient 3, Female, 2 months old at diagnosis, Caucasian
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001252, HP:0001638
(Muscular hypotonia, Cardiomyopathy)
CaseHPOFreeText: floppy baby, no head or neck control
NG tube feeds started at age 1.4 months, currently the patient orally feeds.
Before ERT patient needed oxygen, currently the patient does not need respiratory support.
CaseNotHPOs:
CaseNotHPOFreeText:
Patient ambulates independently
No infusion associated reactions to ERT
CasePreviousTesting: No GAA measurement
Variant: NM_000152.5(GAA):c.236_246del (p.Pro79fs)
ClinVar: 371302
CAID: CA16041880
gnomAD: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
For GAA (Pompe disease) screening
CaseP3-GAA: male, ethnicity = European, country origin = Italy
CasePresentingHPOs:
HPOsFreeText: enzyme activity = 1.97
CaseNotHPOs: HP:0010899, HP:0010916, HP:0003236
CaseAddInfo: known psuedodeficiency alleles (c.1726G>A and c.2065G>A)
CasePreviousTesting: initial and confirmatory DBS, biochemical tests
CaseGenotypingMethod: mutation analyses
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: n/a
C
Case3: Patient ID C, Male, 12 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Hematoma
CaseNotHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0004406, HP:0000225, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, easy bruising, recurrent epistaxis, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemhorrage after dental, hemhorrage after trauma, ear bleeding
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1233C>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399803781
gnomAD: N/A
PreviouslyPublished: PMID: 12424194
J
Case10: Patient ID J, Female, 5 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Related to Patient's I and K (See Table 1)
ParentalGenotype: N/A (Parents are consangenous)
CasePresentingHPOs: HP:0000978, HP:0004406, HP:0000225, HP:0002239
(Easy bruising, recurrent epistaxis, gingival bleeding, GI bleeding
CaseHPOFreeText: Hemorrhage after trauma, hematoma
CaseNotHPOs: HP:0000967, HP:0000979, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrhage after dental, ear bleeding
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602986
gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T
PreviouslyPublished: PMID: 19172520
Family L
Case15: Family L (patient found in the GT database as well) gender and age are not specified here
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225(Epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
PreviouslyPublished: Reference numbers 26,27 in this article
Mila-1
Case8: Patient Mila-1 (found in the GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978 (Bruising)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 25% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1073G>A (p.Arg358His)
LegacyVariant: N/A
ClinVar: 2896
CAiD: CA115839
gnomAD: N/A
PreviouslyPublished: Reference number 19 in this article
GT3
Case33: Patient GT3
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.777+1G>A and the second variant I am not sure how to write out
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623036
gnomAD: MAF in the Latino population is 0.0006774 https://gnomad.broadinstitute.org/variant/17-45363789-G-A
PreviouslyPublished: References 53-55
CW
Case12: Patient CW (can be found in GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000979, HP:0000967, (Ecchymosis, Purpura/petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <1% of normal GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.480C>G (p.Ser160_102del)
LegacyVariant: N/A
ClinVar: 2892 (Arg584Ter)
CAiD: CA115834 and CA399805892
gnomAD: MAF in the East Asian population is 0.0002176 for the Arg584Ter variant and MAF in the East Asian population is 0.00005507 for the other variant https://gnomad.broadinstitute.org/variant/17-42463013-G-C
PreviouslyPublished: Reference number 23 in this article
Supplementary Table S1 & S2 Proband and Variant Information:
Case19: GT22, Male, 13, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000225
(Easy bruising, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.408+11C>A and NM_000419.3:c.1259T>C (p.Val420Ala)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940333 and CA399803733
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case17: GT20, Male, 28, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0005261
(Epistaxis, hemarthrosis)
CaseHPOFreeText: Occasional hematomas
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 10-20% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290946484
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case64: GT67, Male, 61 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother who is now dead (this is all the information we are provided with)
ParentalGenotype: N/A
CasePresentingHPOs:
(Gingival bleeding, epistaxis, bleeding after dental extraction )
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.1618C>T (p.Gln540Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA399802411
gnomAD: MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42457504-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case27: GT31, Female, 13, USA
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000421
(Gingival bleeding and epistaxis)
CaseHPOFreeText: Life-threatening bleeding at onset of menses
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed 5-10% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1771dup (p.Asp591Glyfs*47) and NM_000419.3:c.3061-1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940334 and CA399787972
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case69: GT73, Female, 34 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000421, HP:0000225, HP:0000132
(Ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed nromal to reduced αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.889G>A (p.Gly297Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623074
gnomAD: MAF in the European (non-Finnish) population is 0.00002643 https://gnomad.broadinstitute.org/variant/17-45364547-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case1: GT1, Male, 9, French/African
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0011890, HP:0000421, HP:0000225
(Bruising susceptibility, prolonged bleeding following procedure, epistaxis, gingival bleeding)
CaseHPOFreeText: Tonsilar hemorrhage
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.1913+1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400032825
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case44: GT43b, Male, 11 years old, Morrocan
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister is 43a (See Supplementary Table S1)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000979, HP:0031364, HP:0000967, HP:0030137
(Epistaxis, purpura, ecchymosis, petechiae, prolonged bleeding at circumcision)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.614+1G>T and NM_000212.2:c.683G>A (p.Arg228His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023344 and CA8623025
gnomAD: MAF in the African population is 0.00008012 http://gnomad.broadinstitute.org/variant/17-45363694-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case56: GT57, Female, 10, Argentinian/European
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000967
(Epistaxis, petechia)
CaseHPOFreeText: Hematomas
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.571T>G (p.Phe191Val) and NM_000419.3:c.961G>T (p.Phe191Alafs*32)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805699 and CA399804768
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case44: GT43b, Male, 11 years old, Morrocan
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister is 43a (See Supplementary Table S1)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000979, HP:0031364, HP:0000967
(Epistaxis, purpura, ecchymosis, petechiae)
CaseHPOFreeText: Lots of bleeding at circumcision
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGB3
Variant: NM_000212.2:c.614+1G>T and NM_000212.2:c.683G>A (p.Arg228His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023344 and CA8623025
gnomAD: MAF in the African population is 0.00008012 http://gnomad.broadinstitute.org/variant/17-45363694-G-A
NA
Case13: Patient NA
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: There is a typo in this article, the article states Glu500Ter however it is Gln. NM_000419.3:c.1591C>T (p.Gln531Ter)
LegacyVariant: (p.Gln500Ter)
ClinVar: N/A
CAiD: CA399802478
gnomAD: N/A
12.
Case12: 2 Females, age not specified "Two sisters" is what the Table mentions
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002239
(Gastrointestinal bleeding)
CaseHPOFreeText: Life threatening bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting:
Gene: ITGB3 and ITGA2B
Variant: NM_000212.2:c.392G>C (p.Arg131Pro in ITGB3) and NM_000212.2:c.777+1G>A in ITGB3 and NM_000419.3:c.2264G>A (p.Arg755Gln) in ITGA2B
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622954, CA8623036, CA8602771
gnomAD: MAF in the African population 0.00006152 http://gnomad.broadinstitute.org/variant/17-45361839-G-C , MAF in Latino population 0.0006774 http://gnomad.broadinstitute.org/variant/17-45363789-G-A and MAF in Latino population 0.0001903 (p.Arg775Gln)
24.
Case24: Male, age not specified
DiseaseAssertion: Glanzmann thrombasthenia type 1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe bleeding (See Table 1 for Clinical and Biological Data-- minimal information)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGB3
Variant: NM_000212.2:c.1619G>A (p.Gly540Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400030071
gnomAD: N/A
10.
Case10 : Female, age not specified
DiseaseAssertion: Glanzmann thrombasthenia type 1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGB3
Variant: NM_000212.2:c.940G>T (p.Asp314Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025612
gnomAD: N/A
23.
Case23: Female, age not specified
DiseaseAssertion: Glanzmann thrombasthenia type 1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGB3
Variant: All Table 1 states is "missense mutation" not enough information provided
LegacyVariant: N/A
ClinVar: N/A
CAiD: N/A
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case20b: GT20b, Female, 23 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Family information available in Table1 (sister of proband GT20a)
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0002239, HP:0000132
(Bruising, purpura, ecchymosis, gastrointestinal bleeding, menorrhagia)
CaseHPOFreeText: Post traumatic bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399801310
gnomAD: MAF in Latino population: 0.00003983 https://gnomad.broadinstitute.org/variant/17-42456075-G-A
Supplementary Tables 1 and 2 combined information:
Case35: GT35, Male, 1 year old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364
(Bruising, purpura, ecchymosis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.625-1G>A (c.625-1G>A) and NM_000419.3:c.659A>G (p.Tyr220Cys)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805552 (c.625-1G>A) and CA399805484 (p.Tyr220Cys)
gnomAD: MAF for (p.Tyr220Cys) in the South Asian population 0.00003266 https://gnomad.broadinstitute.org/variant/17-42462543-T-C
Supplementary Tables 1 and 2 combined information:
Case26: GT26, Male, 13 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364
(Bruising, purpura, ecchymosis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (Gln778Pro) and NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: 225393 (p.Gln778Pro)
CAiD: CA290947544 (p.Gln778Pro) and CA8602626 (p.Gln891Ter)
gnomAD: MAF in East Asian population: 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
Supplementary Tables 1 and 2 combined information:
Case12: GT12, Male, 10 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Family history available per Table 1; however, no further information given
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro)
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case29: GT29, Female, 16 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132, HP:0000978, HP:0000979, HP:0031364, HP:0000225
(Menorrhagia, bruising, purpura, ecchymosis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case22: GT22, Female, 16 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132 (Menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case4: GT4, Female, 22 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602626
gnomAD: N/A
Supplemental Table S1:
Cases26-33: Males and Females from France, Spain and Italy and ages are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mild to severe bleeding for probands
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 8-20% αIIbβ3 expression
PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)
CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in the European non finnish population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G
PreviouslyPublished: PMID: 9920835, 12083483, 12424194, 25728920, 20020534
Supplemental Table S1:
Case3: Male, USA, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Severe life threatening bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: >5% αIIbβ3 expression
PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)
CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.1553T>A (p.Ile518Asn) and NM_000419.3:c.1946+3G>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603038 and CA626121071
gnomAD: MAF in the European (non-Finnish) population is 0.000008790 https://gnomad.broadinstitute.org/variant/17-42457661-A-T and MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42456008-C-A
PreviouslyPublished: PMID: 25728920
GT-53
Case43: (GT-53) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623443
gnomAD: MAF in East Asian population: 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T
GT-45b
Case35: (GT-45) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT45-GT48 are related
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1879-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290949031
gnomAD: N/A
GT-29
Case24: (GT-29) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT30 is related to GT29
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1651C>T (p.Arg551Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802348
gnomAD: MAF in the East Asian population is 0.00005045 http://gnomad.broadinstitute.org/variant/17-42457471-G-A
GT-04
Case4: (GT-04) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands 1-9 are related to GT-04 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Mild (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 not observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1210+5G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940251
gnomAD: N/A
GT-07
Case6: (GT-07) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands 1-9 are related to GT-07 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Mild (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 not observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1210+5G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940251
gnomAD: N/A
GT-02
Case2: (GT-02) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands 1-9 are related to GT-02 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: N/A for proband 2 (See Supplemental Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 not observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1210+5G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940251
gnomAD: N/A
Supplementary Table S1:
Case48: GT55, Arg/Brazilian, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.647C>T (p.Ala216Val)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805506
gnomAD: N/A
Supplementary Table S1:
Case49: GT57, Argentinian/European, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.571T>G (p.Phe191Ala/ p.Phe191AlafsTer32) and NM_000419.3:c.961G>T (p.Gly321Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805699 and CA399804768
gnomAD: N/A
Supplementary Table S1:
Case30: GT35a, USA, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B and ITGB3
Variant: ITGA2B: NM_000419.3:c.2264G>A (p.Arg755Gln) NM_000212.2:c.392G>C (p.Arg131Pro) and NM_000212.2:c.777+1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602771, CA8622954, CA8623036
gnomAD: MAF in the Latino population is 0.0001903 https://gnomad.broadinstitute.org/variant/17-42454380-C-T and MAF in the African population is 0.00006152 https://gnomad.broadinstitute.org/variant/17-45361839-G-C and MAF in the African population is 0.0006774 https://gnomad.broadinstitute.org/variant/17-45363789-G-A
Supplementary Table S1:
Case8: GT9, French, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.665T>C (p.Leu222Pro) and NM_000212.2:c.1871G>A (p.Cys624Tyr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224887 and CA400032726
gnomAD: MAF in the European (non-Finnish) population is 0.00006482 https://gnomad.broadinstitute.org/variant/17-45363676-T-C
Supplementary Table S1:
Case18: GT21, French, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs106) and NM_000419.3:c.2864T>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA399791171
gnomAD: N/A
Supplementary Table S1:
Case29: GT34, USA, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1553T>A (p.Ile518Asn) and NM_000419.3:c.1946+3G>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603038 and CA626121071
gnomAD: MAF in the European (non-Finnish) population is 0.000008790 https://gnomad.broadinstitute.org/variant/17-42457661-A-T and MAF in the African population for NM_000419.3:c.1946+3G>T is 0.000 https://gnomad.broadinstitute.org/variant/17-42456008-C-A
Supplementary Table S1:
Case43: GT50, French, age and gender not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.1260G>A (p.Lys376_Thr420del)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623200
gnomAD: MAF in the African population is 0.00004005 https://gnomad.broadinstitute.org/variant/17-45368454-G-A
Supplementary Table S1:
Case21: GT24, French Gypsy, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A (p.Val513Leufs*71)
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
Case21: Patient GI, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGB3
Variant: c.728T>T (Unregistered) GT database has the same variant listed and it won't show up in CAR
LegacyVariant: ^
ClinVar: ^
CAiD: ^
gnomAD: ^
Case14: Patient LRI, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: (p.Arg674Arg)
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G
Case6: Patient FF, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.855dup
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940766
gnomAD: N/A
Case18: Patient ME, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.2929C>T (p.Arg977Ter)
LegacyVariant: (p.Arg946Ter)
ClinVar: N/A
CAiD: CA8602528
gnomAD: MAF in the South Asian population is 0.00003266 https://gnomad.broadinstitute.org/variant/17-42452041-G-A
Case2: Patient PF, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.416C>T (p.Ala139Val)
LegacyVariant: (p.Ala108Val)
ClinVar: N/A
CAiD: CA399806036
gnomAD: N/A
Case13: Patient BM, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Cys705Arg)
LegacyVariant: (p.Arg674Arg)
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G
GT 03
Case14: GT03, Female, India, age of onset is 6 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.166-14C>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622881
gnomAD: MAF in the South Asian population is 0.00003274 https://gnomad.broadinstitute.org/variant/17-45360706-C-A
GT 06
Case2: GT06, Female, India, age of onset is 13 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.245dup (p.Gly83ArgfsTer19)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940723
gnomAD: N/A
GT 42
Case30: GT42, Female, India, age of onset is 26 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.356G>A (p.Arg119Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8622925
gnomAD: MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A
GT 21
Case23: GT21, Male, India, age of onset is 33 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.921C>A (p.Tyr307Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025209
gnomAD: N/A
GT 60-1
Case35: GT60-1, Female, India, age of onset is 27 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.428T>G (p.Leu143Trp)
LegacyVariant: N/A
ClinVar: 13567
CAiD: CA123252
gnomAD: MAF in the Other population is 0.0001629 https://gnomad.broadinstitute.org/variant/17-45361875-T-G
GT 11
Case19: GT11, Female, India, age of onset is 12 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.115T>G (p.Cys39Gly)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400031666
gnomAD: N/A
The propositus
Case1: Female, age and ethnicity is previously described in Ruan et al, 1993, but access not available to this article
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: The propositus' twin brother was also affected
ParentalGenotype: Article mentions, "Thus the two affected members are double heterozygote having inherited two different abnormal GPIIb alleles, one from the father and the other from the mother"
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding time > 15 minutes
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Absent or reduced platelet GPIIb and GPIIIa assessed by Western blotting
PlateletAggregation: Absent platelet aggregation in response to ADP, epinephrine, and collagen and normal aggregation in response to ristocetin
CasePreviousTesting: PCR was used to amplify the defective segment of the GPIIb gene
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: c.9644C>T
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
M9
Case9: Patient M9, Male, French Gypsy, age is not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Figure 2 for pedigree
ParentalGenotype: Unaffected parents see pedigree Fig 2
CasePresentingHPOs: N/A
CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)
PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
The proband was a 27-year old Danish woman
Case1: Female, 27 years old, Danish
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Information on father, mother, brother and sister. (See Figure 1 for pedigree)
ParentalGenotype: Pedigree from Figure 1 shows Father to have (p.Asn331Ser) and mother has (p.Arg786Trp) variant.
CasePresentingHPOs: HP:0000978, HP:0001934, HP:0006298
(Bruising, prolonged bleeding after minor trauma, prolonged bleeding after dental extraction)
CaseHPOFreeText: Lifelong bleeding history
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: αIIbβ3 expression and activation and αvβ3 expression were assessed by flow cytometry (See Figure 1 and 2 for results)
PlateletAggregation: Platelet aggregation was impaired in response to all stimuli except ristocetin, with low-normal response to collagen
CasePreviousTesting: To identify DNA variants, all exons of ITGA2B and ITGB3 were analyzed by Sanger sequencing
Gene: ITGB3
Variant: NM_000212.2:c.2356C>T (p.Arg786Trp) an NM_000212.2:c.992A>G (p.Asn331Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400034866 (p.Arg786Trp) and CA400025729 (p.Asn331Ser)
gnomAD: MAF for (p.Arg786Trp) in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-45387559-C-T
The patient is a 2-year-old female from China
Case1: Female, 3 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A (No information about the family was available since the child was adopted)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421 (Epistaxis)
CaseHPOFreeText: Mucocutaneous hemorrhages, prolonged bleeding time
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Protein expression was estimated by flow cytometry and western blot analysis. The analysis revealed less than 10% of surface expression of alphaIIbbeta3 relative to control platelets. (See Fig 2)
PlateletAggregation: Platelet aggregation in response to ADP, collagen, adrenaline, and arachidonic acid was less than 5% that of control platelets, and no clot retraction was observed. Ristocetin-induced platelet agglutination and plasma fibrinogen content were within the normal range.
CasePreviousTesting: Sequencing for mutations was carried out by direct sequencing of PCR overlapping fragments of reversed transcribed αIIb and β3 mRNA.
Gene: ITGA2B
Variant: NM_000419.3:c.2829C>T (p.Pro943Leu), NM_000419.3:c.2621T>G (p.Ile874Ser), NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: (p.Ile843Ser) and (p.Arg553Ter) and (p.Pro912Leu)
ClinVar: 2891, 2892
CAiD: CA500263536, CA115831, CA115834
gnomAD: MAF in the European (Finnish) population is 0.4395 https://gnomad.broadinstitute.org/variant/17-42453065-A-C and MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
16CabGT-16
Case16: (Proband CabGT-16), Male, age not specified, North African
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed 2% GPIIb and 10% GPIIIa surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.2870C>T (p.Ser957Leu)
LegacyVariant: N/A
ClinVar: 2902
CAiD: CA115850
gnomAD N/A
14CabGT-14
Case14: (Proband CabGT-14), Female, age not specified, North African
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% GPIIIa and GPIIb surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.2748_2757del (p.T917Sfs181)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290946532
gnomAD MAF in the African population is 0.0001150 https://gnomad.broadinstitute.org/variant/17-42452449-GCACCACAGTA-G
22CabGT-22
Case22: (Proband CabGT-22), Female, age not specified, South American
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression:
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGB3
Variant: NM_000212.2:c.431T>G (p.Met144Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224645
gnomAD N/A
10
Case10: (Proband CabGT-10) Female, age not specifie,d North African
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% GPIIIa and GPIIb surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.1878G>C (p.Gln626His)
LegacyVariant: N/A
ClinVar: 2903
CAiD: CA115852
gnomAD N/A
19CabGT-19
Case19: (Proband CabGT-19), Gender, age and ethnicity is not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: N/A
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGB3
Variant: NM_000212.2:c.166-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224483
gnomAD N/A
4
Case4: Female, 35 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A per Table 1
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Prolonged ivy bleeding times, bleeding diathesis since early childhood
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Surface expression of αIIbβ3 was analyzed by flow cytometry which was 10-20% of normal
PlateletAggregation: Aggregation in response to ADP, epinephrine and collagen was absent but normal in response to ristocetin
CasePreviousTesting: Nucleotide sequences of the αIIb and β3 coding regions were determined by direct sequencing of RT-PCR products from platelet RNA.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro)
LegacyVariant: (p.Gln747Pro)
ClinVar: 225393
CAiD: CA290947544
gnomAD: MAF in the East Asian population is 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
cases 3
Case3: Female, 32 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A per Table 1
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Prolonged ivy bleeding times, bleeding diathesis since early childhood
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Surface expression of αIIbβ3 was analyzed by flow cytometry which was 10-20% of normal
PlateletAggregation: Aggregation in response to ADP, epinephrine and collagen was absent but normal in response to ristocetin
CasePreviousTesting: Nucleotide sequences of the αIIb and β3 coding regions were determined by direct sequencing of RT-PCR products from platelet RNA.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro)
LegacyVariant: (p.Gln747Pro)
ClinVar: 225393
CAiD: CA290947544
gnomAD: MAF in the East Asian population is 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
M4
Case12: (M4) Female, 17 years old, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Failed to express alphaIIbbeta3 on the surface of their platelets
Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)
CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD N/A
M10
Case18: (M10) Female, 37, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Failed to express alphaIIbbeta3 on the surface of their platelets
Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)
CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD N/A
A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a Chinese patient with Glanzmann's thrombasthenia.
Case1: Female, 20 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Parents were heterozygous for mutation (See Fig 3)
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000967, HP:0000979, HP:0000132
(Epistaxis, gingival bleeding, petechiae, purpura, severe menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Surface GPIIb/IIIa expression was < 15% of normal
Platelet Aggregation: Absent platelet aggregation in response to ADP, epinephrine, or collagen but normal response to ristocetin
CasePreviousTesting: Direct sequencing of PCR amplified cDNA and GPIIIa exon VIII indicated that the patient was homozygous for the mutation
Gene: ITGB3
Variant: NM_000212.2:c.1199G>A (p.Cys400Tyr)
LegacyVariant: (p.Cys374Tyr)
ClinVar: 13562
CAiD: CA123244
gnomAD N/A
M/22
Case4: Male, 22 years old, Tamil Nadu India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0006298, HP:0000421, HP:0002239, HP:0000225
(Prolonged bleeding after tooth extraction, epistaxis, GI bleeding, gingival bleeding)
CaseHPOFreeText: Bleeding during tooth extraction
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1 for values
PlateletAggregation: See Table 1 for values
CasePreviousTesting: PCR amplification of ITAG2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1162G>A (p.Gly388Ser)
LegacyVariant: (p.Gly357Ser)
ClinVar: N/A
CAiD: CA8603212
gnomAD: N/A
M/20
Case9: Male, 20 years old, Tamil Nadu India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000225, HP:0006298
(Epistaxis, ecchymosis, gingival bleeding, prolonged bleeding after dental extraction)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1 for values
PlateletAggregation: See Table 1 for values
CasePreviousTesting: PCR amplification of ITAG2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.2489T>G (p.Leu830Arg)
LegacyVariant: (p.Leu799Arg)
ClinVar: N/A
CAiD: CA8602667
gnomAD: MAF in the South Asian population is 0.00003270 https://gnomad.broadinstitute.org/variant/17-42453313-A-C
M/11
Case7: Male, 1 years old, West Bengal India
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0006298, HP:0000967
(Gingival bleeding, prolonged bleeding after tooth extraction, petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1 for values
PlateletAggregation: See Table 1 for values
CasePreviousTesting: PCR amplification of ITAG2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1651C>T (p.Arg551Trp)
LegacyVariant: (p.Arg520Trp)
ClinVar: N/A
CAiD: CA399802348
gnomAD: MAF in the East Asian population is 0.00005045https://gnomad.broadinstitute.org/variant/17-42457471-G-A
GT70
Case25: (GT70) Gender, age, and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGA2B
Variant: NM_000419.3:c.2673_2674dup and NM_000419.3:c.1424_1427dup
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940687 and CA8603099
gnomAD MAF in the South Asian population is 0.0001960 https://gnomad.broadinstitute.org/variant/17-42457979-C-CACCT
GT30
Case28: (GT30) Gender, age and ethnicity are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother and father are heterozygous for the mutation
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGB3
Variant: NM_000212.2:c.674del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940689
gnomAD N/A
GT10
Case20: (GT10)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGB3
Variant: NM_000212.2:c.59T>C (p.Leu20Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400028389
gnomAD N/A
GT72
Case17: (GT72) Gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGB3
Variant: NM_000212.2:c.1641C>G (p.Cys547Trp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400030171
gnomAD N/A
58
Case9: (GT58), Gender, age and ethnicity not reported
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene: ITGA2B
Variant: NM_000419.3:c.1028T>C (p.Leu343Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804619 (p.Leu343Pro)
gnomAD N/A
one of the patient affected
Case1: Gender, age, and ethnicity not reported here
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.800G>A (p.Gln267Glu)
LegacyVariant: (p.Gln236Glu)
ClinVar: N/A
CAiD: CA399805147
gnomAD: N/A
PreviouslyPublished: PMID: 12083483 (Access not available to this article)
For the patient with Glanzmann thrombasthenia
Case1: Gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.262C>T (p.Arg88Ter)
LegacyVariant: (p.Arg62Ter)
ClinVar: N/A
CAiD: CA400020703
gnomAD: MAF in the Other population is 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T
A 66-year-old male
Case1: Male, 66 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Information of proband's child in Figure 2
ParentalGenotype: N/A
CasePresentingHPOs: HP:0011890
(Prolonged bleeding following procedure)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: On admission to the hospital, proband had no sign or symptoms of bleeding.
ProteinExpression: In comparison to normal platelets, very low αIIbβ3 (1,053 ± 544 copies/platelet, n=3) and αvβ3 (755 ± 180 copies/platelet, n=3) expression were measured on the cell surface expression of our patient’s platelets.
PlateletAggregation: Light transmission aggregometry showed his platelets were unable to respond to ADP, collagen, arachidonic acid, and epinephrine; however, platelet agglutination in response to ristocetin was normal.
CasePreviousTesting: To identify the molecular genetic defect in this patient, we isolated genomic DNA from the patient’s leukocytes and amplified all exons of ITGA2B and ITGB3 gene by PCR.
Gene: ITGB3
Variant: NM_000212.2:c.1697G>A (p.Gly566Asp)
LegacyVariant: (p.Gly540Asp)
ClinVar: N/A
CAiD: CA400032338
gnomAD: N/A
GT12
Case#: 7 year old, female
Disease: Glazmann's Thrombasthenia
CasePresentingHPOs: HP:0000967, HP:0000978, HP:0000225, HP:0004406, HP:0006298, HP:0001892
PlateletAgreggation: Defective response to ADP, Adrenaline, Collagen, Arachidonic acid. Normal response to Ristocetin.
GenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes for mutational analysis of the αIIb and β3 genes by DNA sequencing
Allele 1:
ClinVar: 2892
CAID: CA115834
Variant: NM_000419.5:c.1750C>T
GnomAD: East Asian Population 0.0002176 (4/18386)
Allele 2:
ClinVar: 225393
CAID: CA290947544
Variant: NM_000419.5:c.2333A>C
GnomAD: East Asian at a rate of 0.0001087 (2/18394)
ExpressionEvidence:Flow Cytometry of platelet integrin: 94.9% B3 expression, 5.66% A2B expression
GT15
Case#: 6 year old, male
Disease: Glazmann's Thrombasthenia
CasePresentingHPOs: HP:0000967, HP:0000978, HP:0004406, HP:0000225, HP:0006298, HP:0001892, HP:0002239
PlateletAgreggation: Defective response to ADP, Adrenaline, Collagen, Arachidonic acid. Normal response to Ristocetin.
GenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes for mutational analysis of the αIIb and β3 genes by DNA sequencing
Allele 1:
ClinVar: 2892
CAID: CA115834
Variant: NM_000419.5:c.1750C>T
GnomAD: East Asian Population 0.0002176 (4/18386)
Allele 2:
ClinVar: 953046
CAID: CA399802348
Variant: NM_000419.5:c.1651C>T
GnomAD: Highest in East Asian population at a rate of 0.00005045 (1/19820)
ExpressionEvidence:Flow Cytometry of platelet integrin: 99.2% B3 expression, 3% A2B expression
2
Case2: Female, Iraq, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0002249
(Epistaxis, gingival bleeding, menorrhagia, melena)
CaseHPOFreeText: Petechial rash, post-partum bleeding, colon angiodysplasia, haematemesis
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)
LegacyVariant: (p.Asp651Glufs*3)
ClinVar: N/A
CAiD: CA915940605
gnomAD: N/A
9
Case9: Male, Iraq, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364, HP:0030137, HP:0002573
(Epistaxis, gingival bleeding, ecchymosis, prolonged bleeding following circumcision, rectal bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)
LegacyVariant: (p.Asp651Glufs*3)
ClinVar: N/A
CAiD: CA915940605
gnomAD: N/A
Patient 1
Case1: Male, 2 years old, Korean
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Figure 1 shows haplotype analysis
CasePresentingHPOs: HP:0000978, HP:0000967
(Easy bruising, petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analyses revealed markedly decreasedCD41/CD61 expression (<1%) in Patient 1 (type I GT).
PlateletAggregation: Platelet aggregation tests were performed to evaluate responses to ADP, collagen, epinephrine, and ristocetin agonists
CasePreviousTesting: Polymerase chain reaction for all exons ofITGA2Band/orITGB3were performed using primers. Sequence analysis was performed with reference to M_000419.3 andNP_000410.2 forITGA2Band NM_000212.2 and NP_000203.2 for ITGB3.
Gene: ITGB3
Variant: NM_000212.2:c.1913+5G>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623377
gnomAD: MAF in the East Asian population is 0.0001633 http://gnomad.broadinstitute.org/variant/17-45376901-G-T
Patient 2
Case2: Male, 38 years old, Korean
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Figure 1 shows haplotype analysis
CasePresentingHPOs: HP:0004406, HP:0000225
(Recurrent epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analyses revealed markedly decreasedCD41/CD61 expression (<1%) in Patient 2 (type I GT).
PlateletAggregation: Platelet aggregation tests were performed to evaluate responses to ADP, collagen, epinephrine, and ristocetin agonists
CasePreviousTesting: Polymerase chain reaction for all exons ofITGA2Band/orITGB3were performed using primers. Sequence analysis was performed with reference to M_000419.3 andNP_000410.2 forITGA2Band NM_000212.2 and NP_000203.2 for ITGB3.
Gene: ITGB3
Variant: NM_000212.2:c.1913+5G>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623377
gnomAD: MAF in the East Asian population is 0.0001633 http://gnomad.broadinstitute.org/variant/17-45376901-G-T
F1.III.4
Case#: 26 year old female
Disease: Glazmann's Thrombasthenia Like Syndrome
CasePresentingHPOs: HP:0000978, HP:0001873
Bruising susceptibility, Thrombocytopenia,
CaseNotHPOs: HP:0004846
FamilyInfo: Three sisters all with thrombocytopenia and easy bruising/nose bleeding during infancy. Mother and grandmother had identical phenotype. Disease segregation with thrombocytopenia and decreased GPIIb/IIIa in the affected patients was confirmed. Pedigree figure 1.
PlateletAgreggation: Famiy member studied: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, Ristocetin not assessed in individual per supplementary table.
GenotypingMethod: genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.
ClinVar: 50233
CAID: CA10575573
Variant: NM_000419.5:c.3076C>T
GnomAD: Not Found
ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 45%, CD61 (GPIIIa) 56%, and CD42b (GPIb) 155%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).
F6.II.4
Case#: Female, 30 (age of diagnosis)
Disease: Glazmann's Thrombasthenia Like Syndrome
CasePresentingHPOs: HP:0000225, HP:0000978, HP:0006298
Gingival bleeding, Bruising susceptibility, Prolonged bleeding after dental extraction
CaseNotHPOs: NA
FamilyInfo: Pedigree figure 1. Father and two daughters affected.
PlateletAgreggation: Family member studied: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination
GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.
ClinVar: Not Found
CAID: CA400034251
Variant: NM_000212.3:c.2236A>C (ITGB3)
GnomAD: Not Found
ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 38%, CD61 (GPIIIa) 41%, and CD42b (GPIb) 85%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).
HS
Case6: Patient HS, gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 6
PlateletAggregation: See Table 6
CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries
Gene: ITGA2B
Variant: NM_000419.3:c.1878G>C
LegacyVariant: N/A
ClinVar: 2903
CAiD: CA115852
gnomAD: N/A
GE
Case8: Patient GE, gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 6
PlateletAggregation: See Table 6
CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries
Gene: ITGA2B
Variant: NM_000419.3:c.2051T>G (p.Leu684Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399799849
gnomAD: N/A
A 30year old primigravida type-I GT patient
Case1: 30 year old, Female (primigravada), ethnicity not reported
DiseaseAssertion: Type-1 Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: See Table 1 (Father wild type and mother has frameshift mutation)
CasePresentingHPOs: HP:0000132 (Menorrhagia)
CaseHPOFreeText: Vaginal bleeding, haematochezia
CaseNotHPOs: N/A
CaseNotHPOsFreeText: Proband did not have any bleeding manifestations at the age of 16
ProteinExpression: Using flow cytometry, the test sample (normal plate-lets+patient plasma) showed only 28% GPIIb-IIIa expression as compared to 81.4% GPIIb-IIIa expression seen in the control sample(normal platelets+control plasma) (Fig. 1B) confirming the presence of GPIIbIIIa antibodies in patient plasma.
PlateletAggregation: Absent aggregation in response to ADP and collagen and normal response to ristocetin (Platelet aggregation information found in Table 1)
CasePreviousTesting: The mutation analysis was performed by Sanger sequencing of both ITGA2B and ITGB3 genes, which showed a frameshift mutation: c.1230_1230delC, cDNA.1262_1262delC (Y411Tfs*20) due to a single base deletion in exon 13 of ITGA2B
Gene: ITGA2B
Variant: NM_000419.3:c.1230del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940214
gnomAD: N/A
The patient
Case1: Male, elderly (specific age not specified), from Argentina (specific ethnicity not specified)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mild bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed patient's platelet aIIbb3 content was 40–50% of the usual range
PlateletAggregation: Platelets failed to aggregate with all physiological agonists including thrombin
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2332T>C (p.Ser778Pro)
LegacyVariant: (p.Ser752Pro)
ClinVar: 13556
CAiD: CA123230
gnomAD: N/A
PreviouslyPublished: Caen, 1985; Chenet al, 1992 (PMID's not available at this time, go to these articles from this curated paper)
GT1
Disease: Glazmann's Thrombasthenia
Case: 11 year old female French Gypsy
CasePresentingHPOs: HP:0001975
(Decreased platelet glycoprotein IIb-IIIa)
GenotypingMethod:Genotyping analysis of the HPA-1 system by high resolution melting analysis (methods not provided, cited article I don't have access too)
ClinVar: 2895
CAID: CA10575473
Variant: NM_000419.5:c.1544+1G>A
GnomAD: Not found
ExpressionEvidence: Failed to express αIIbβ3 integrin on their platelet surface (methods not provided cited article no access too)
3/M
Case#: Patient ID 6, Male 3 years old. North Indian
Disease: Glazmann's Thrombasthenia
CasePresentingHPOs: HP:0003540, HP:0000967, HP:0002239
Impaired platelet aggregation, Petechiae, Gastrointestinal hemorrhage
PlateletAgreggation: LTA with ADP, Epi, Coll, AA, and Ristocetin: Impaired with all agonists
GenotypingMethod: Next generation sequencing. Sanger sequencing used to confirm pathogenic variants
ClinVar:1691486
CAID: CA399794330
Variant: NM_000419.5:c.2578C>T
GnomAD: NA
ExpressionEvidence:Flow Cytometry for platelet expression of GPIIb/IIIa in CD41a 0% and CD61 0%.
The patient, a 33-mo-old boy
Case1: Male, 33 months old, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother heterozygous for the c.1544+1G>A variant
CasePresentingHPOs: HP:0000967, HP:0000979, HP:0002094
(Petechiae, purpura, dyspnea,
CaseHPOFreeText: Hypoxia
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis showed GPIIb/IIIa expression to be 22.6.
PlateletAggregation: Platelets failed to aggregate in response to ADP, epinephrine, collagen, calcium ionophore, and TRAP; however, ristocetin-induced aggregation was normal
CasePreviousTesting: Sequencing of coding regions of ITGA2B and ITGB3 genes was performed
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
male patient
Case1: Male, French, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Son was heterozygous carriers of the p.Leu196Pro mutation (Sister died from nasal bleeding when she was a child)
ParentalGenotype: Mother is heterozygous for p.Leu196Pro mutation (Father not alive)
CasePresentingHPOs: HP:0000421 (Epistaxis)
CaseHPOFreeText: Lifelong history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Expression showed 8% of normal platelet content for αIIbβ3
PlateletAggregation: Absent aggregation to physiologic agonists
CasePreviousTesting: Screened exons and splice sites of ITGB3 and ITGA2B genes of patient by single-strand conformation polymorphism analysis of PCR products.
Gene: ITGB3
Variant: NM_000212.2:c.665T>C (Leu222Pro) and NM_000212.2:c.1871G>A (p.Cys624Tyr)
LegacyVariant: p.Leu196Pro and p.Cys598Tyr
ClinVar: N/A
CAiD: CA291224887 and CA400032726
gnomAD: N/A
The propositus is a 49 year-old French woman
Case1: Female, 49 years old, French
DiseaseAssertion: Glanzmann thrombasthenia (diagnosed when 5 years old)
FamilyInfo: A brother died from hemorrhage when he was 4 years old, but an adult sister has never experienced untoward bleeding. (Case History Supp Table 1)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0004406, HP:0000132, HP:0000225, HP:0000790
(Easy bruising, recurrent epistaxis, menorrhagia, gingival bleeding, hematuria
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis showed no biding of P2 and AP-2, two MoAbs recognizing alphaIIbBeta3 and a very weak binding of MoAbs to Beta3 to platelets of the proband
PlateletAggregation: Platelet function testing confirmed an absence of aggregation to ADP, collagen, arachidonic acid and thrombin but the response to ristocetin was normal (Case History Supp Table 1)
CasePreviousTesting: Direct sequencing of all exons and splice sites of ITGA2B (30 exons) and ITGB3 (15 exons) was performed by the French National Sequencing Center. Briefly, exons and flanking regions of ITGA2B and ITGB3 were amplified by PCR with a high fidelity Taq polymerase permitting large fragment amplification. PCR fragments were sequenced.
Gene: ITGB3
Variant: (p.Pro189Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224669
gnomAD: MAF in European (non-Finnish) population is 0.00002638 http://gnomad.broadinstitute.org/variant/17-45362012-C-T
An 18-year-old woman was found to have GT
Case1: Female 18 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0025636 (Endometriosis)
CaseHPOFreeText: "Endometriosis and bleeding"
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: See Table 1 (information provided)
PlateletAggregation: N/A
CasePreviousTesting: Sequenced GPIIIa by PCR
Gene: ITGB3
Variant: NM_000212.2:c.166-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA291224483
gnomAD: N/A
Table 3 Molecular Diagnosis of Patients with Glanzmann Thrombasthenia:
Case2: GT-2, age, gender, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: Segregation analysis confirmed in presence of heterozygous mutations in this proband.
ParentalGenotype: Although segregation analysis confirmed, we do not know which variant in particular came from mom or dad.
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients presented with a variable bleeding diathesis; most patients had epistaxis (54%), cutaneous bleeding (58%), and menorrhagia (100% of women) while other common symptoms (oral cavity, GI, following dental extraction of mild injuries, postpartum, or hematomas) were in general milder. There is no specific phenotypes attached to probands in this paper.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that αIIbβ3 expression was less than 5%
PlateletAggregation: There was severely impaired aggregation in response to all physiological agonists, and ristocetin induced platelet agglutination was normal or reduced to some extent.
CasePreviousTesting: Total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Then, using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing. Every mutation found in cDNA was confirmed in DNA samples.
Gene: ITGA2B
Variant: NM_000419.3:c.2473_2481delinsTCACCTGGTC and NM_000419.3:c.641T>C (p.Leu214Pro)
LegacyVariant: p.Leu183Pro
ClinVar: (p.Leu214Pro is 2901)
CAiD: CA915940289 and CA115848
gnomAD: N/A
7
Case7: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0005542, HP:0000132, HP:0000421, HP:0000978
(Prolonged clotting, menorrhagia, epistaxis, easy bruising)
CaseHPOFreeText: Bleeding time greater than 20 minutes
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1899del (p.Cys633TrpfsTer17)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940223
gnomAD: N/A
4
Case4: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0000978, HP:0000132, HP:0000421, HP:0000979
(Easy bruising, menorrhagia, epistaxis, purpura)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGB3
Variant: NM_000212.2:c.1303G>T (p.Glu435Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400028645
gnomAD: N/A
13
Case12: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1555C>T (p.Gln519Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802559
gnomAD: N/A
Patient Osaka-5
Case1: (Osaka-5) Female, 33 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that the amount of αIIbβ3 expressed was about 6% of normal platelets
PlateletAggregation: N/A
CasePreviousTesting: Coding regions of ITGA2B and ITGB3 cDNAs were amplified by RT PCR
Gene: ITGB3
Variant: NM_000212.2:c.917A>C (p.His306Pro)
LegacyVariant: (p.His280Pro)
ClinVar: N/A
CAiD: CA291224999
gnomAD: https://gnomad.broadinstitute.org/variant/17-45364575-A-C
13
Case13: Female, 9 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002248, HP:0000421, HP:0031364 (Haematemesis, epistaxis, ecchymosis)
CaseHPOFreeText:
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.2674del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940582
gnomAD: N/A
12
Case12: Male, 3 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Sibling is proband number 11 in this article
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002249, HP:0000421 (Melena, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.1600+1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802454
gnomAD: N/A
3
Case3: Gender or age not specified, Thai ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Parental information available in Table 2
ParentalGenotype: Father: p.Arg782Ter/WT and Mother: Unavailable
Note: No parental consanguinity
CasePresentingHPOs: N/A
CaseHPOFreeText: The article does not mention specific bleeding phenotypes for each of the 4 probands in the article, rather, there is a general statement that says: "The common presentations included recurrent epistaxis, bleeding in oral cavity, and easy-bruising spontaneously or after trauma"
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinEpression: General statement from the article that states that flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression for all probands.
PlateletAggregation: The platelet aggregation test was typically defective with all physiological agonists except ristocetin, for all patients.
CasePreviousTesting: Whole exome sequencing was performed on the 30 exons of ITGA2B and 15 exons in ITGB3. PCR and direct sequencing were then performed in the DNA samples of the patients and their available parents to verify the presence of the identified mutations.
Gene: ITGA2B
Variant: NM_000419.3:c.2344C>T (p.Arg782Ter) and NM_000419.3:c.2915dup (p.Leu973Alafs*63)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399796586 (p.Arg782Ter) and CA8602531 (p.Leu973Alafs*63)
gnomAD: MAF for (p.Leu973Alafs*63) in East Asian population 0.0001088 http://gnomad.broadinstitute.org/variant/17-42452054-C-CG
A rare case of Glanzmann's thrombasthenia and factor VII deficiency due to a combination of pathogenic and non-pathogenic gene variants
PMID: 31777146
Disease: Glazmann's Thrombasthenia type 1 and factor 7 deficiency
Case: 13 year old male, from non-consanguineous
CasePresentingHPOs: HP:0011889, HP:0000978, HP:0031364,
GenotypingMethod: Direct sequencing of all coding, splice site and promoter regions of F7 and ITGA2B and ITGB3 genes. Heterozygous for two ITGB3 variants predicted to be deleterious in silico.
First heterozygous mutation:
ClinVar: Not found
CAID: CA400022111
Variant: NM_000212.3:c.473A>T
GnomAD: Not found
Second heterozygous mutation:
ClinVar: Not found
CAID: CA400033092
Variant: NM_000212.3:c.2027A>C
GnomAD: Not found
PlateletAggregation: Platelet aggregation studies showed absent aggregation with adenosine diphosphate (ADP), collagen and was reduced with ristocetin
ExpressionEvidence: flow cytometry studies for platelet receptors showed absence of αIIbβ3 integrin and normal levels of GPIb and GPIX receptors
Recently, we reported the case of an 8-year-old boy with a variant form of GT
Case1: Male, 8 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Sister had no bleeding tendency (all the information given in the previously published article cited in this annotation)
ParentalGenotype: Parental mutations shown in Fig. 3 A and B
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Tonsilar bleeding
CaseNotHPOs: HP:0000979
(Purpura)
CaseNotHPOFreeText: N/A
ProteinExpression: Western blotting indicated that the proband's platelets contained no normal GPIIb, but showed a trace amount of an abnormal GPIIb (-6% with respect to the GPIIb level in a normal individual).
PlateletAggregation: Decreased aggregation in response to ADP, collagen and epinephrine but a normal ristocetin-induced aggregation (this information was obtained from the previously published article cited at in this annotation)
CasePreviousTesting: Genomic DNA fragments containing exons of the GPIIb gene were amplified by PCR
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.2602-3C>G
LegacyVariant: N/A
ClinVar: 2892 and 2893
CAiD: CA115834 and CA10575472
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A and MAF in the East Asian population is 0.00006523 https://gnomad.broadinstitute.org/variant/17-42453087-G-C
PreviouslyPublished: PMID: 1891767