Case: Male, Spanish, onset at 57yo with pelvic weakness

CasePresentingHPOs: HP:0003236, HP:0002522, HP:0003184, HP:0012515, HP:0003749, HP:0003700, HP:0005144, HP:0002151, HP:0030232, HP:0009058

HPOsFreeText: weakness of hip adduction and shoulder abduction, abolished lower limb reflexes. CK = 500-800 U/L, lactate = 27.0 U/L, GOT = 50 U/L, GPT = 69 U/L, LDH = 449 U/L, aldolase = 8.7 U/L, myopathic motor unit action potentials with early recruitment and spontaneous activity (mainly in quadriceps), asymmetric septal left ventricular hypertrophy with preserved ventricular function, atrophy of both biceps and deltoid muscles, fibrillary deposits in cytoplasm, focal disorganization of sarcomeres, decrease in GAA inhibitory activity (0.64-0.68 μmol/L/h)

CaseNotHPOs: HP:0001283, HP:0002093, HP:0003326, HP:0002487

NotHPOsFreeText:

CaseAddInfo: daughter also underwent genetic testing which showed she was a heterozygous carrier for the same variant. She presented with decreased GAA activity in DBS and isolated lymphocytes.

CasePreviousTesting: blood laboratory exams, electromyography study, echocardiogram, biopsy of biceps and deltoid muscles, histochemical staining which showed no abnormalities, electron microscopy, DBS, enzyme activity analyzed in isolated lymphocytes (confirmed decreased GAA activity)

CaseGenotypingMethod: n/a

Variant: NM_000152.3:c.1249A>C

CAID: CA401365271, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401365271

gnomAD: n/a

CaseLOPD-5: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.1 (nmol · h−1 · mg−1), Mean percentage of normal 4.4%

GenotypingMethod: Newborn Screening Panels

Variant: 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

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseLOPD-1: 3 weeks diagnosis

HPOsFreeText: GAA activity 3.2 (nmol · h−1 · mg−1), Mean percentage of normal 4.5%

GenotypingMethod: Newborn Screening Panels

Variant: 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

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseIOPD-4: 3 min diagnosis

CasePresentingHPOs: HP:0003236, HP:0001638 (Increased serum CK, Cardiomyopathy)

HPOsFreeText: GAA activity 0.6 (nmol · h−1 · mg−1), Mean percentage of normal 0.9%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.271G>A (p.Asp91Asn)

ClinVar: 4020 https://www.ncbi.nlm.nih.gov/clinvar/variation/4020/

gnomAD: European (Non-Finnish) 0.03291, Overall 0.02049 http://gnomad.broadinstitute.org/variant/17-78078656-G-A

Variant2: NM_000152.4:c.307T>G (p.Cys103Gly)

ClinVar: 92483 https://www.ncbi.nlm.nih.gov/clinvar/variation/92483/

gnomAD: European (non-Finnish) 7.874e-6, Overall 3.578e-6 http://gnomad.broadinstitute.org/variant/17-78078692-T-G

Variant3: NM_000152.4:c.1000G>T (p.Gly334Cys)

ClinVar: 284864 https://www.ncbi.nlm.nih.gov/clinvar/variation/284864/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature claims Variant 1 and 2 are in cis

PMID: 31256280

Gene: GAA

Disease: Pompe Disease

Inheritance: Autosomal Recessive

Patient2: 76yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0000822, HP:0002870, HP:0020038

HPOsFreeText: morning headaches, GAA = 13%, BMI = 23.6, right vertebral artery dominant, nucleo-capsular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 33yr disease duration

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

Patient9: 54yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0003141, HP:0002870

HPOsFreeText: morning headache, GAA = 7%, smoker, BMI = 23.3, normal CTA, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 29yr 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

PMID: 33732206

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case#: Subject number 35, female, 35 years (diagnosis), 35 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

Case6: Male, 65 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 95 meters, Forced Vital Capacity at 36%

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.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

Case20: Female, 63 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 10 meters, Forced Vital Capacity at 57%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.1748C>T (p.Ser583Phe)

CAID: CA401369174 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1748C%3ET

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.2014C>T (p.Arg672Trp)

ClinVar: 188773 https://www.ncbi.nlm.nih.gov/clinvar/variation/188773/

gnomAD: South Asian 3.355e-5, Overall 8.290e-6 http://gnomad.broadinstitute.org/variant/17-78086800-C-T

CaseAddInfo: Late Onset Pompe Disease

Case#: Subject number 1(I), male, 21 days (start of ERT), 31 months (report)

DiseaseAssertion: Infantile Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002870 (obstructive sleep apnea), HP:0001639 (hypertrophic cardiomyopathy), HP:0200128 (biventricular hypertrophy), HP:0030234 (Highly elevated creatine kinase)

CaseHPOFreeText: moderately to severely decreased left ventricular systolic wall motion, moderate hypertrophy of the left ventricle, severe right ventricular hypertrophy, requires BiPAP at night, patient receives physical, occupational, and speech therapies.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 923 U/L (60–305 U/L is normal), AST: 103 U/L (30–100 U/L is normal), BNP: 1080 pg/mL (0.0–100.0 pg/mL), Hex4: 24.7 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 0.65 micromole/L/h and GAA activity #2 (NBS) 0.22 in dried blood spots (>2.10 micromole/L/h is normal). 4.4 in confirmatory testing (>6.7 is normal).

Variant 1: NM_000152.5(GAA):c.759delC

Variant 1 ClinVarID: 837937

Variant 1 CAid: CA916082438

Variant 2: NM_000152.5(GAA):c.1551+1G>C

Variant 2 ClinVarID: 554983

Variant 2 CAid: CA401367167

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case21: 12.5 years onset, 13 years diagnosis, 13 years report

CasePresentingHPOs: HP:0003236 (Increased serum CK)

HPOsFreeText: Asymptomatic hyperCKemia

CaseAddInfo: Late-Onset Pompe Disease, Gender reported as "W"

CaseC: Female, 2 months onset, 3 months diagnosis

CasePresentingHPOs: HP:0001270, HP:0003324, HP:0001638 (Motor delay, Generalized weakness, Cardiomyopathy)

HPOsFreeText: CRIM positive

CaseNotHPOs: HP:0100543, HP:0002540, HP:0004887 (Cognitive impairment, Inability to walk, Respiratory failure requiring assisted ventilation)

CaseAddInfo: Infantile-Onset Pompe Disease

Case2: Male, Danish, 39 years report, 20 years onset

CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)

HPOsFreeText: 6-min walk test achieved 441 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 4.1/3.7 (L)

NotHPOsFreetext: Not on ERT

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.2331+2T>G

CAID: CA401324960 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2331%2B2T%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case5: Female, French, 30 years report, 27 years onset

HPOsFreeText: 6-min walk test achieved 488 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 2.4/2.2 (L), Has started ERT

CaseNotHPOs: HP:0008956 (Thigh muscle atrophy)

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

Variant1: NM_000152.4:c.1655T>C (p.Leu552Pro)

ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C

Variant2: NM_000152.4:c.1688A>T (p.Gln563Leu)

CAID: CA401368995 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1688A%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 5, Gender N/A, Onset at 5-6 months. Death at 1.5 years of age, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165, HP:0001270, HP:0001252, HP:0001714, HP:0002090

(Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval, Motor delay, Muscular hypotonia, Ventricular hypertrophy, Pneumonia )

CaseHPOFreeText: Death from heart failure and pneumonia

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0% of normal control value.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant 1: NM_000152.5(GAA):c.1538A>G (p.Asp513Gly)

ClinVar: 638014

CAID: CA401367134

gnomAD: N/A

ParentalGenotype: Both parents carried the .1538A>G (p.Asp513Gly) variant in the GAA gene. There was no parental consanguinity

PreviouslyPublished: N/A

Case#: Patient 9, female, diagnosed 2014 (not given age of diagnosis), age 34 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: None given

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>G (unclear variant nomenclature)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:c.1802C>T

Variant 2 ClinVarID: 194154

Variant 2 CAid: CA274982

ParentalGenotype: Not provided

Case#: case 1, male, 3 months old at diagnosis, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0001252 (cardiomyopathy, muscular hypotonia)

CaseHPOFreeText: (Associated with Pompe Disease): Interventricular septum hypertrophy, increased serum CK, increased serum tryptase

CaseHPOFreeText: (Infussion associated reactions) Urticarial rash, unresponsive to antihistamines and corticosteroids

CaseNotHPOs:

CaseNotHPOFreeText: Infusion associated reactions are not associated with an IgE mediated mechanism.

CasePreviousTesting:

GAA activity on fibroblast is 0.8 nmol/mg prot/h with a reference range of 64.4 ± 22.9 nmol/mg prot/h

GAA activity on lymphocytes is 2.2 nmol 4 Mu/mg prot/h with a reference range of 21.4 ± 6.2 nmol 4 Mu/mg prot/h

Variants:<br /> Variant 1: NM_000152.5(GAA):c.236_246del (p.Pro79fs)

ClinVar: 371302

CAID: 16041880

Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

ClinVar:279811

CAID: 8815429

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 11, male, 68 years (report), 30s years (onset), 55 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000360 (tinnitus), HP:0002650 (scoliosis), HP:0000939 (osteoporosis), HP:0000821 (hypothyroidism)

CaseHPOFreeText: on BiPAP, ambulatory, assistive device (walker, cane)

CaseNotHPOs: HP:0000365, HP:0002617, HP:0009830, HP:0100647, HP:0010788, HP:0001638 (hearing loss, aneurysm, 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.1951_1952delGGinsT (p.Gly651SerfsTer?)

Variant 2 ClinVarID: 633225

Variant 2 CAid: CA913191010

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 13, male, 50 years (report), 42 years (onset), 45 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

*CasePresentingHPOs:* HP:0000360 (tinnitus), HP:0002650 (scoliosis), HP:0001638 (cardiomyopathy), HP:0001638 (Graves disease), HP:0010788 (testicular cancer), HP:0000821 (hypothyroidism)

CaseHPOFreeText: on BiPAP, ambulatory

CaseNotHPOs: HP:0009830, HP:0000939, HP:0000365, HP:0002617 (peripheral neuropathy, osteoporosis, hearing loss, aneurysm)

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.525_526delTG (p.Asn177ProfsTer11)

Variant 2 ClinVarID: 189057

Variant 2 CAid: CA274328

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient2: Male, 40yo at diagnosis, 63yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies tire = 1:6400, enzyme (μmol/g/h) = 0.36 (3-20), NIV used before and after ERT

CaseNotHPOs:

NotHPOsFreeText: mobility aid not used

CaseAddInfo: 23yr disease duration, variants in trans

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_000152.3:c.2135T>C

CAID: CA401370560, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2135T%3EC

gnomAD: n/a

Case#: Patient 6, Female, 5.5 months old at diagnosis, Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001252, HP:0001638

(Muscular hypotonia, Cardiomyopathy)

CaseHPOFreeText:

Previous to ERT, patient was invasively ventilated, and had . Also Aspiration and penetration with feeding and started on NG tube feeds at baseline

Current patient has marked axial and peripheral hypotonia, G-tube feeds and requires BiPAP at night. Patient has near-complete lower extremity immobility

CaseNotHPOs: N/A

CaseNotHPOFreeText: Antigravity movement in arms

CasePreviousTesting: N/A

Variant: NM_000152.5(GAA):c.525_526del (p.Asn177fs) Please double check

ClinVar: 189057

CAID: CA274328

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

CaseD: 17 years onset

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.1754+1dup

CAID: CA891862615 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1754%2B1dup

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Patient8: Female, Serbian, mid 70s

CasePresentingHPOs: HP:0003325

HPOsFreeText: Normal CK levels

CaseNotHPOs: HP:0003236, HP:0002093

CaseAddInfo: late onset

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.2051C>G

CAID: CA401370340, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370340

gnomAD: n/a

Variant2: 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

Case#: Subject number 12, male, 52 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), 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 0.48 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.1889-1G>A

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA401369820

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient7: male, 40yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 25.1 / 22.9 / 22.9, WGMS = 3 / 3 / 3

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

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_000152.3:c.1291_1299del

CAID: CA658795248, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795248

gnomAD: n/a

CaseLP-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.61, MS/MS ennzyme activity at 0.01

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: 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

Variant2: 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

Variant3: NM_000152.4:c.1075+1G>T

CAID: CA401364842 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1075%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Suspected Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

Case89

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.877G>A (p.Gly293Arg)

ClinVar: 4036 https://www.ncbi.nlm.nih.gov/clinvar/variation/4036/

gnomAD: Latino 5.704e-5, Overall 1.807e-5 http://gnomad.broadinstitute.org/variant/17-78081617-G-A

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

PatientF1P4: Male, birth onset, prenatal diagnosis, Caucasian

HPOsFreeText: IOPD was confirmed with decreased acid GAA on a lymphocyte assay (6 nmol/hr/mg, control 36 nmol/hr/mg) and on a foreskin fibroblast sample,

CaseAddInfo: First cousin twice removed of F1P1, Mother carries both c.1880C>T and VUS c.1642G>T mutations in cis

Case#: Patient 3, male, 21 year old, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: No family history of muscle disease

CasePresentingHPOs: HP:0003236, HP:0100284

(Elevated serum creatine kinase, EMG: myotonic discharges

CaseHPOFreeText: Mild weakness (4/5) of iliopsoas muscles

Myotonic discharges in the lumbar paraspinal muscles

Elevated aspartate aminotransferase of 172 I/U ( Normal range 19–55 I/U)

Elevated alanine aminotransferase of 203 I/U (Normal range 19–72 I/U)

Serum CK was elevated at 1,373 U/L (normal range 70–185 U/L)

CaseNotHPOs:

CaseNotHPOFreeText: Normal alkaline phosphatase and γ-glutamyl transpeptidase levels.

Liver ultrasound and biopsy at an outside facility were normal

CasePreviousTesting: GAA level was 1.4 pmol/punch/h (normal range 10–49 pmol/punch/h)

Variant 1: NM_000152.5(GAA):c.-32-13T>G

ClinVar: 4027

CAID: CA116606

gnomAD: Hughest population MAF= 0.005541 (Ashkenazi Jewish)

Variant 2: NM_000152.5(GAA):c.877G>A (p.Gly293Arg)

ClinVar: 4036

CAID: CA116622

gnomAD: Highest population MAF= 0.00005704 (Latinos)

ParentalGenotype:N/A

PreviouslyPublished:N/A

Patient18: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

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.796C>T (p.Pro266Ser)

ClinVar: 556117, https://www.ncbi.nlm.nih.gov/clinvar/variation/556117/

gnomAD: n/a

Supplementary Table S1 & S2 Proband and Variant Information:

Case41: GT41b, Male, 13 years old, Chinese

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected sister is 41a in this study (See Supplemental Table S1)

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000978

(Epistaxis, easy bruising)

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.91del (p.Ala31Profs2) and NM_000419.3:c.2915dup (p.Leu973Alafs63)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913203486 and CA8602531

gnomAD: MAF in the East Asian population is 0.0001088 http://gnomad.broadinstitute.org/variant/17-42452054-C-CG

Supplementary Table S1 & S2 Proband and Variant Information:

Case72: GT76, Male, 54 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0002239, HP:0032551

(Gi bleeding, hemorrhoids)

CaseHPOFreeText: Moderate bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Type unknown for this proband

PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGA2B

Variant: NM_000419.3:c.2421G>A (p.Trp807Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399796017

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case8: GT9, Male, 86, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421

(Epistaxis)

CaseHPOFreeText: Moderate mucocutaneous bleeding

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: 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 0.00006482 http://gnomad.broadinstitute.org/variant/17-45363676-T-C

Supplementary Table S1 & S2 Proband and Variant Information:

Case42: GT42, Male, 15 years old, Egyptian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0012541, HP:0002239, HP:0031364, HP:0030137

(Cephalohematoma, GI bleeding, ecchymosis, prolonged bleeding after 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: ITGA2B

Variant: NM_000419.3:c.2148dup (p.Leu717Alafs*3)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940304

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case33: GT36a, Female, 49 years old, Spanish

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected brother who is proband 36b and affected sister who is proband 36c in this study

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225

(Epistaxis, gingival bleeding)

CaseHPOFreeText: Bleeding at the onset of menses

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.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399806881 and CA913184940

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case26: GT30, Female, age not specified, Caucasian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected brother (See Supplementary Table 1)

ParentalGenotype: N/A

CasePresentingHPOs:

(Epistaxis, GI bleeding)

CaseHPOFreeText: Diffuse bruising mainly with trauma

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: ITGB3

Variant: NM_000212.2:c.777+1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623036

gnomAD: MAF in the Latino population is 0.0006774 http://gnomad.broadinstitute.org/variant/17-45363789-G-A

Supplementary Table S1 & S2 Proband and Variant Information:

Case55: GT55, Female, 28, Argentinian/Brazilian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Has an affected sister (this is all the information we are provided with)

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0000421

(Gingival bleeding, epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed 11-22% 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.647C>T (p.Ala216Val)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805506

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case35: GT36c, Female, 47 years old, Spanish

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected sister who is proband 36 a and affected brother proband 36b

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000132, HP:0011891

(Menorrhagia, post-partum hemorrhage)

CaseHPOFreeText: Intra-abdominal hemorrhage and bleeding after trauma

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.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1de (p.Arg480Serfs*106)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399806881 and CA913184940

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case7: GT8, Male, 82 at death, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978, HP:0000421, HP:0002239

(Easy bruising, epistaxis, GI bleeding

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed 10-15% 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.2348+5G>C (p.Ser756Gly783delInsArg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290947484

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case47: GT47, Male, 11 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Severe mucocutaneous bleeding

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.832del (p.Asp278Ilefs*101)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940374

gnomAD: N/A

Case3: (GT-03) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands 1-9 are related to GT-03 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 (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

Case26: (GT-31) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT31-GT34 are related to GT31

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available for this proband (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 the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T

Case46: (GT-57) Male, 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

Case52: (GT-71) Gender, age, or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not given (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.1142C>T (p.Thr381Ile)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399804396

gnomAD: N/A

Case28: (GT-33) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT31-GT34 are related

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: ITGB3

Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623443

gnomAD: MAF in the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T

Case55: (GT-74) Gender, age, or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not given (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.985A>G (p.Asn329Asp)

LegacyVariant: N/A

ClinVar: 323865

CAiD: CA8623107

gnomAD: MAF in Other population 0.0005534 http://gnomad.broadinstitute.org/variant/17-45367092-A-G

Case4: GT-4, gender, age, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents

CasePresentingHPOs: N/A

CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed αIIbβ3 expression to be <5%

PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.

CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples

Gene: ITGB3

Variant: M_000212.2:c.647A>G (p.Tyr216Cys)

LegacyVariant: (p.Tyr190Cys)

ClinVar: N/A

CAiD: CA400023432

gnomAD: N/A

Case3: GT-3, gender, age, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type II

FamilyInfo: N/A

ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents

CasePresentingHPOs: N/A

CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed αIIbβ3 expression between 5% and 20%

PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.

CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples

Gene: ITGA2B

Variant: NM_000419.3:c.2113T>C (p.Cys705Arg)

LegacyVariant: (p.Cys674Arg) +31=705

ClinVar: N/A

CAiD: CA8602816

gnomAD: MAF in European (non-Finnish) population is 0.000008792 http://gnomad.broadinstitute.org/variant/17-42455140-A-G

PreviouslyPublished PMID: 9920835

Case2: GT-2, gender, age, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents

CasePresentingHPOs: N/A

CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed <5% αIIbβ3 expression

PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.

CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples

Gene: ITGA2B

Variant: NM_000419.3:c.641T>C (p.Leu214Pro) and NM_000419.3:c.2473_2481delinsTCACCTGGTC c.2473_2481delinsTCACCTGGTC

LegacyVariant: (p.Leu183Pro) + 31= 214

ClinVar: 2901

CAiD: CA115848 and CA915940289

gnomAD: N/A

PreviouslyPublished PMID: 9473221 (p.Leu214Pro)

Case1: GT-1, gender, age, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type II

FamilyInfo: N/A

ParentalGenotype: Segregation analysis confirmed the presence of heterozygous mutations in carrier parents

CasePresentingHPOs: N/A

CaseHPOFreeText: Article mentions patients presented with variable bleeding diathesis and Table 1 shows the several phenotypes that were seen among the cohort of 13 patients in this study (this article does not state a specific bleeding phenotype for each proband) "Most of the patients had gross blood loss due to epistaxis (54%), cutaneous bleeding (58%) and menorrhagia (100% of women), while other common symptoms (oral cavity, gastrointestinal, following dental extraction or mild injuries, postpartum, or hematomas) were in general milder."

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry revealed αIIbβ3 expression between 5% and 20%

PlateletAggregation: Article mentions the disorder was indentified by platelet testing consisting in severely impaired aggregation in response to all physiological agonists and also TMA (See Table 4). Ristocetin-induced platelet aggregation was normal or reduced to some extent.

CasePreviousTesting: To detect mutations in ITGA2B or ITGB3, total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing, and every mutation found in cDNA was confirmed on DNA samples

Gene: ITGB3

Variant: NM_000212.2:c.448A>G (p.Met150Val) and NM_000212.2:c.774_775del (p.Cys258Ter)

LegacyVariant: (p.Met124Val)

ClinVar: N/A

CAiD: CA8622961 and CA915940285

gnomAD: MAF in South Asian population is 0.00003266 http://gnomad.broadinstitute.org/variant/17-45361895-A-G

PreviouslyPublished PMID: 15583747 (p.Met124Val)

Case1: Male, 5 years old, Swiss

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Family pedigree provided in Figure 1- blood samples for the study were obtained from the patient, his parents and 5 other members of his family and none of the other studied family members have experienced abnormal bleeding

ParentalGenotype: Studied and no mutation detected

CasePresentingHPOs: N/A

CaseHPOFreeText: Frequent mucocutaneous bleeding with transfusion being required shortly after birth

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: <2% of the normal platelet content of GPIIb-IIIa as determined by flow cytometry

PlateletAggregation: Absence of platelet aggregation in response to ADP, epinephrine, thrombin and collagen; however, normal platelet agglutination with ristocetin

CasePreviousTesting: Using a PCR‐SSCP procedure and direct sequence analysis of PCR‐amplified DNA fragments, we have examined all exons and splice sites of the GPIIb and GPIIIa genes

Gene: ITGA2B

Variant: NM_000419.3:c.1063G>A (p.Glu355Lys) and NM_000419.3:c.1787T>C (p.Ile596Thr)

LegacyVariant: (p.Glu324Lys) and (p.Ile565Thr)

ClinVar: 2899 and 2900, respectively

CAiD: CA115844 and CA115846, respectively

gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T and the MAF in the European (non-Finnish) population is 0.0001325 https://gnomad.broadinstitute.org/variant/17-42457148-A-G

PMID: 23912132

Genes: ITGA2B and ITGB3

HGNC: 6138 and 6156

NoEvidence: This article discusses GT; however no probands with variants in ITGA2B and ITGB3 are discussed.

Note: Annotated on the PubMed Abstract because the journal this article is in, Blood Coagulation and Fibrinolysis does not work properly.

Case10: Patient FC

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs:

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: NM_000419.3:c.2540T>C (p.Leu847Pro)

LegacyVariant: (p.Leu816Pro)

ClinVar: N/A

CAiD: CA399794666

gnomAD: MAF in the African population is 0.00006443 https://gnomad.broadinstitute.org/variant/17-42453262-A-G

Case12: Patient Ssab

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: ITGB3

Variant: NM_000212.2:c.1955A>T (p.His652Leu)

LegacyVariant: (p.His626Leu)

ClinVar: N/A

CAiD: CA400032927

gnomAD: N/A

Case16: Patient TG

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: NM_000419.3:c.3061-1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399787972

gnomAD: N/A

Supplementary Table S1:

Case2: GT3, 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.353T>A (p.Leu118His) and NM_000212.2:c.709_710del (p.Ser237Cysfs*13) and NM_000212.2:c.1732G>A (p.Asp578Asn)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA291224511 (p.Leu118His) and CA8623029 (p.Ser237Cysfs*13) and CA8623343 (p.Asp578Asn)

gnomAD: MAF in the European (non-Finnish) population in (p.Ser237Cysfs*13) is 0.00001796 https://gnomad.broadinstitute.org/variant/17-45363717-CAG-C and MAF in the Other population for (p.Asp578Asn) is 0.0008149 https://gnomad.broadinstitute.org/variant/17-45376715-G-A

Supplementary Table S1:

Case58: GT, 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.1413C>G (p.Tyr471Ter) and other other variant is stated as "LR deletion" so I will note it as an Unknown Variant

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290950376

gnomAD: MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C

Supplementary Table S1:

Case3: GT4, 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

Supplementary Table S1:

Case57: GT67, 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.Arg480SerfsTer106) 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:

Case25: GT28, French/Syrian, 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: All the supplemental table says is "LR dup" no other information is provided here (I will note this as Unregistered-please feel free to change this by commenting and letting me know)

LegacyVariant: N/A

ClinVar: N/A

CAiD: N/A

gnomAD: N/A

Supplementary Table S1:

Case19: GT22, 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: ITGA2B

Variant: NM_000419.3:c.408+11C>A and NM_000419.3:c.1259T>C (p.Va;420Ala)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940333 and CA399803733

gnomAD: N/A

Supplementary Table S1:

Case36: GT42, Canadian/Egypt, 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.2148dup (p.Leu717AlafsTer3)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940304

gnomAD: N/A

Supplementary Table S1:

Case42: GT49, French/Spanish, 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.1440-13_1440-1del (p.Arg480SerfsTer106) and NM_000419.3:c.2113T>C (p.Cys705Arg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913184940 and CA8602816

gnomAD: MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G for the (p.Cys705Arg) variant

Supplementary Table S1:

Case45: GT53, Argentina/Brazil, 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.356G>A (p.Arg119Gln) and NM_000212.2:c.1697G>A (p.Gly566Asp)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8622925 and CA400032338

gnomAD: MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A

PMID: 11988077

Gene: ITGA2B and/or ITGB3

HGNC: 6138 and 6156

NoEvidence: This article does not mention GT probands with variants in ITGA2B and/or ITGB3 therefore there is insufficient evidence. However, the present study used blood samples from 2 patients with GT; therefore, the gene name and HGNC are included in this annotation

PMID: 8111390

Gene: ITGA2B

HGNC: 6138

PMID: 14499243

Gene: ITGA2B and/or ITGB3

HGNC: 6138 and 6156

InsufficientEvidence: This mentions GT case reports; however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence

Supplementary Tables 1 and 2 combined information:

Case18: Gt18, Male, 20 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Available per Table 1; however, very minimal information

ParentalGenotype: Parents are consanguineous, no other genotype information available

CasePresentingHPOs: HP:0000421

(Epistaxis)

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 (p.Gln891Ter)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case36: GT36, Male, 8 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, HP:0000421, HP:0002239

(Bruising, purpura, ecchymosis, epistaxis, gastrointestinal bleeding)

CaseHPOFreeText: Intestinal intrussusception

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: ITGB3

Variant: NM_000212.2:c.1913+5G>T (c.1913+5G>T)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623377

gnomAD: MAF in the East Asian population 0.0001633 https://gnomad.broadinstitute.org/variant/17-45376901-G-T

Supplementary Tables 1 and 2 combined information:

Case27: GT27, Male, 29 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Available per Table 1; however, very minimal information

ParentalGenotype: Parents are not consanguineous, no other genotype information available

CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364

(Bruising, purpura, ecchymosis)

CaseHPOFreeText: Post traumatic hemorrhage

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 (p.Gln778Pro) This article is not completed-Meera

LegacyVariant: N/A

ClinVar: 225393

CAiD: CA290947544

gnomAD: MAF in East Asian population: 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G

Supplementary Tables 1 and 2 combined information:

Case10: GT10, Male, 8 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, HP:0000421

(Bruising, purpura, ecchymosis, epistaxis)

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.2236G>T (p.Glu746Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399798321

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case15a: Male, 15 years old, brother to GT15b

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Available per Table 1, brother to GT15b

ParentalGenotype: Parents are not consanguineous, no other genotype information available

CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225

(Bruising, purpura, ecchymosis, epistaxis, 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, a small response to 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: ITGB3

Variant: NM_000212.2:c.1525del (p.Gln509Argfs*160) and NM_000212.2:c.1199G>A (p.Cys400Tyr)

LegacyVariant: N/A

ClinVar: 13562 (p.Cys400Tyr)

CAiD: CA915940237 (p.Gln509Argfs*160) and CA123244 (p.Cys400Tyr)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case1: GT1, Female, 5 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, HP:0000421

(Bruising, purpura, ecchymosis, epistaxis)

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.1051C>T (p.Arg351Ter) and NM_000419.3:c.2029G>A (p.Glu677Lys)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290954030 (p.Arg351Ter) and CA399800002 (p.Glu677Lys)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case39: GT39, Male, 25 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Available per Table 1; however, very minimal information

ParentalGenotype: Parents are not consanguineous, no other genotype information available

CasePresentingHPOs: HP:0100309 (Subdural hematoma)

CaseHPOFreeText: Post traumatic hemorrhage

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Showed 50-100% (variant) 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.2570G>T (p.Cys857Phe) and NM_000419.3:c.1769G>A (p.Arg590Gln)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399794409 (p.Cys857Phe) and CA8602943 (p.Arg590Gln)

gnomAD: MAF for (p.Arg590Gln) in the Latino population 0.0002314 https://gnomad.broadinstitute.org/variant/17-42457166-C-T

Supplementary Tables 1 and 2 combined information:

Case34: GT34, Male, 3 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, HP:0000421,HP:0000225

(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)

CaseHPOFreeText: Post traumatic hemorrhage

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.432G>A (p.Trp144Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805999

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case14: GT14, Female, 5 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, HP:0000421, HP:0000225

(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)

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

LegacyVariant: N/A

ClinVar: 225393

CAiD: CA290947544

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case7: GT7, Female, 31 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:0000132

(Bruising, purpura, ecchymosis, epistaxis, 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.1652G>A (p.Arg551Gln)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8602986 (p.Arg551Gln)

gnomAD: MAF in South Asian population: 0.00006536 https://gnomad.broadinstitute.org/variant/17-42457470-C-T

Supplementary Tables 1 and 2 combined information:

Case5: GT5, Female, 25 years old; however, now deceased

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Not available per supplementary table 1

ParentalGenotype: Parents are consanguineous, no other genotype information available

CasePresentingHPOs: HP:0000132, HP:0000421, HP:0002239, HP:0002170

(Menorrhagia, epistaxis, gastrointestinal bleeding, intracranial hemorrhage)

CaseHPOFreeText: Post traumatic hemorrhage

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) and NM_000419.3:c.2159T>C (p.Leu720Pro)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA115834 (p.Arg584Ter) and CA399798955 (p.Leu720Pro)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case2: GT2, 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, HP:0000421

(Bruising, purpura, ecchymosis, epistaxis)

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 East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A

Case21: (GT62) Gender, age and ethnicity are not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs:

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.1559del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940684

gnomAD N/A

Case15: (GT24) 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.953T>C (p.Leu318Ser)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400025639

gnomAD MAF in the European Finnish population is 0.00004620 https://gnomad.broadinstitute.org/variant/17-45367060-T-C

Case1: Gender or age not specified, Thai ethnicity

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: Father: p.Arg584Ter/WT and Mother: p.Leu973Alafs*63/WT (See Table 2)

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.1750C>T (p.Arg584Ter) and NM_000419.3:c.2915dup (p.Leu973Alafs*63)

LegacyVariant: N/A

ClinVar: 2892 (p.Arg584Ter)

CAiD: CA115834 (p.Arg584Ter) and CA8602531 (p.Leu973Alafs*63)

gnomAD: MAF for (p.Arg584Ter) in the East Asian population 0.0002176 http://gnomad.broadinstitute.org/variant/17-42457372-G-A and MAF for (p.Leu973Alafs*63) in the East Asian population 0.0001088 http://gnomad.broadinstitute.org/variant/17-42452054-C-CG

PMID: 7530476

Gene: ITGA2B and/or ITGB3

HGNC: 6138 and 6156

InsufficientEvidence: This mentions a Glanzmann thrombasthenia patient; however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence

Case1: Female, 22 years old, Portuguese

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Also studied were the probands mother (I.2) father (1.1) and sister (II.2) and only her sister has reported excessive bleeding, although her platelet aggregation tests were normal for all of them (See Fig. 2A)

ParentalGenotype: Parents were heterozygous

CasePresentingHPOs: HP:0000967

(Petechia)

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Western blot expression study shows classic type 1 GT with less than 5% surface expression of aIIb3

PlateletAggregation: Platelet aggregation was absent with physiological agonists but agglutination with ristocetin was normal

CasePreviousTesting: Examined each of the 30 exons of beta3 gene and each of the 15 exons of the aIIb gene for migration changes in PCR-SSCP analysis. Each PCR reaction was controlled by electrophoresis of the amplified fragments on 1.5% agarose gels

Gene: ITGB3

Variant: NM_000212.2:c.1924G>T (p.Glu642Ter)

LegacyVariant: N/A

ClinVar: 13565

CAiD: CA123249

gnomAD: N/A