9
Case9: 0.4 years diagnosis, Germany
CasePresentingHPOs: HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)
HPOsFreeText: 18 BNP (pg/ml), 2.42 IVS (d) z score, 1.82 IVS (s) z score, Heart Failure at NYHA Class 1
NotHPOsFreeText: No left-ventricular outflow tract obstruction
CaseAddInfo: Infantile-Onset Pompe Disease
CaseLP-3: Female, Taiwan, Birth diagnosis
HPOsFreeText: 4MU enzyme activity at 0.49, MS/MS ennzyme activity at 0.10
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.1004G>A (p.Gly335Glu)
ClinVar: 180142 https://www.ncbi.nlm.nih.gov/clinvar/variation/180142/
gnomAD: Not in gnomAD
CaseAddInfo: Suspected Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis
CaseLP2-6: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.10 umol/hr/L, Serum CK at 103 U/L
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.1004G>A (p.Gly335Glu)
ClinVar: 180142 https://www.ncbi.nlm.nih.gov/clinvar/variation/180142/
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis
CaseOPOPD-64: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.72 umol/hr/L
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
Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)
ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/
gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype
CaseOPOPD-43: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.20 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.1082C>T (p.Pro361Leu)
ClinVar: 403712 https://www.ncbi.nlm.nih.gov/clinvar/variation/403712/
gnomAD: Latino 5.798e-5, Overall 1.203e-5 http://gnomad.broadinstitute.org/variant/17-78082294-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 allele and One Pseudodeficency Mutation allele
CaseOPTPD-78: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.91 umol/hr/L
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
Variant2: NM_000152.4:c.2214G>A (p.Trp738Ter)
ClinVar: 370223 https://www.ncbi.nlm.nih.gov/clinvar/variation/370223/
gnomAD: East Asian 5.437e-5, Overall 3.986e-6 http://gnomad.broadinstitute.org/variant/17-78090791-G-A
CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy
CaseOPOPD-61: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.63 umol/hr/L
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
Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)
ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/
gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype
CaseOPOPD-63: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.05 umol/hr/L
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
Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)
ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/
gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype
CaseOPOPD-72: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.31 umol/hr/L
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
Variant2: NM_000152.4:c.2662G>T (p.Glu888Ter)
ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 2 other patients have the same genotype
CaseOPOPD-38: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.56 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: 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
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 allele and One Pseudodeficency Mutation allele
CaseOPTPD-1: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.47 umol/hr/L
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
Variant2: NM_000152.4:c.546+5G>T
ClinVar: 557811 https://www.ncbi.nlm.nih.gov/clinvar/variation/557811/
gnomAD: East Asian 4.978e-4, Overall 3.824e-5 http://gnomad.broadinstitute.org/variant/17-78078936-G-T
CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with only one copy, 2 other patients have the same genotype
CaseIP2-4: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.08 umol/hr/L, Serum CK at 385 U/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.1194+2T>C
ClinVar: 370077 https://www.ncbi.nlm.nih.gov/clinvar/variation/370077/
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
CaseLP2-10: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.06 umol/hr/L, Serum CK at 670 U/L
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.2662G>T (p.Glu888Ter)
ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T
CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis
CaseOPOPD-62: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.85 umol/hr/L
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
Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)
ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/
gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype
LOPD-8
CaseLOPD-8: 6 weeks diagnosis
HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.1%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.2051C>T (p.Pro684Leu)
ClinVar: 285821 https://www.ncbi.nlm.nih.gov/clinvar/variation/285821/
gnomAD: European (Non-Finnish) 1.631e-4, Overall 8.195e-5 http://gnomad.broadinstitute.org/variant/17-78087027-C-T
Variant2: NM_000152.3: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.W746C possible, below is considered the most likely
Variant3: NM_000152.4:c.2238G>C (p.Trp746Cys)
ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/
gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C
CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 2 and 3 are in cis
LOPD-17
CaseLOPD-17: 6 weeks diagnosis
HPOsFreeText: GAA activity 6.5 (nmol · h−1 · mg−1), Mean percentage of normal 9.2%
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.1552-3C>G
ClinVar: 419722 https://www.ncbi.nlm.nih.gov/clinvar/variation/419722/
gnomAD: European (Non-Finnish) 2.713e-4, Overall 1.344e-4 http://gnomad.broadinstitute.org/variant/17-78084737-C-G
CaseAddInfo: Late Onset Pompe Disease
PD/Pathogenic-2
CasePD/Pathogenic-2: 3 weeks diagnosis
HPOsFreeText: GAA activity 8.8 (nmol · h−1 · mg−1), Mean percentage of normal 12.4%
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.2646+2T>A
ClinVar: 188924 https://www.ncbi.nlm.nih.gov/clinvar/variation/188924/
gnomAD: Not in gnomAD
CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis
LOPD-19
CaseLOPD-19: 2 weeks diagnosis
HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.8%
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
Variant2: NM_000152.4:c.1115A>T (p.His372Leu)
ClinVar: 370483 https://www.ncbi.nlm.nih.gov/clinvar/variation/370483/
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease
PD/VOUS-3
CasePD/VOUS-3: 2 weeks diagnosis
HPOsFreeText: GAA activity 11.3 (nmol · h−1 · mg−1), Mean percentage of normal 15.8%
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
Variant3: NM_000152.4:c.664G>A (p.Val222Met)
ClinVar: 290223 https://www.ncbi.nlm.nih.gov/clinvar/variation/290223/
gnomAD: South Asian 5.393e-3, Overall 6.931e-4 http://gnomad.broadinstitute.org/variant/17-78079665-G-A
CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis
LOPD-18
CaseLOPD-18: 2 weeks diagnosis
HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.0%
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.2188G>T (p.Glu730Ter)
ClinVar: 495665 https://www.ncbi.nlm.nih.gov/clinvar/variation/495665/
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease
PD/VOUS-2
CasePD/VOUS-2: 2 weeks diagnosis
HPOsFreeText: GAA activity 16.6 (nmol · h−1 · mg−1), Mean percentage of normal 23.3%
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.2069C>T (p.Pro690Leu)
ClinVar: 424308 https://www.ncbi.nlm.nih.gov/clinvar/variation/424308/
gnomAD: East Asian 1.077e-4, Overall 2.337e-5 http://gnomad.broadinstitute.org/variant/17-78087045-C-T
CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis
LOPD-14
CaseLOPD-14: 2 weeks diagnosis
HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%
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.2509C>T (p.Arg837Cys)
ClinVar: 456408 https://www.ncbi.nlm.nih.gov/clinvar/variation/456408/
gnomAD: European (Non-Finnish) 4.676e-5, Overall 2.487e-5 http://gnomad.broadinstitute.org/variant/17-78092019-C-T
CaseAddInfo: Late Onset Pompe Disease
3.1 Description of the study population
Patient1: IOPD Group, 25days old
CasePresentingHPOs:
HPOsFreeText: LDH = 480 U/L, CK = 1273 U/L, ALT = 52 U/L, AST = 102 U/L, Mann-Whitney Test = 3
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2238G>C (p.Trp746Cys)
ClinVar: 265160, https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/
gnomAD: 0.0003083, https://gnomad.broadinstitute.org/variant/17-78090815-G-C
Variant2: NM_000152.4(GAA):c.2237G>A (p.Trp746Ter)
ClinVar: 280063, https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: 0.000003988, https://gnomad.broadinstitute.org/variant/17-78090814-G-A
8
Case#: Patient 8, male
CasePresentingHPOs: HP:0003236, HP:0003325
CaseAddInfo: 30yo at onset, 35yo at diagnosis
VariantAllele1: 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
VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del
ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/
gnomAD: n/a
11
Case#: Patient 11, male
CasePresentingHPOs: HP:0003236, HP:0003325
CaseAddInfo: 24yo at onset, 47yo at diagnosis
VariantAllele1: 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
VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del
ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/
gnomAD: n/a
VIII
CaseVIII: Early adult onset, 56 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326, HP:0003198 (Proximal muscle weakness, Increased serum CK, Easy fatiguability, Myalgia, Myopathy)
HPOsFreeText: GAA activity from dried blood spot: 0.13%, Forced Vital Capacity Seated: 2480 (75%), Plasma CK 2.5-5x Normal, 6-Minute Walking Test: 385 min
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease, Reduced staining for dystrophin in patient VIII suggested Becker dystrophy before LOPD diagnosis
3
CaseVI,3: Adult onset, 64 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003236 (Proximal muscle weakness, Abnormal respiration, Increased serum CK)
HPOsFreeText: GAA activity from dried blood spot: 0.16%, Forced Vital Capacity Seated: 1550 (48%), Plasma CK 2.5-5x Normal
CaseAddInfo: Late-Onset Pompe Disease
Case23: Male, 77 years report
HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 120 meters, Forced Vital Capacity at 40%
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.925G>A (p.Gly309Arg)
ClinVar: 188797 https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/
gnomAD: Ashkenazi Jewish 1.010e-4, Overall 2.860e-5 http://gnomad.broadinstitute.org/variant/17-78081665-G-A
CaseAddInfo: Late Onset Pompe Disease
c.2608C > T(p.Arg870*)
Case78
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.2608C>T (p.Arg870*)
ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/
gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 http://gnomad.broadinstitute.org/variant/17-78092118-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.2512C > T(p.Gln838*)
Case42
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.2512C>T (p.Gln838*)
ClinVar: 92479 https://www.ncbi.nlm.nih.gov/clinvar/variation/92479/
gnomAD: African 6.177e-5, Overall 3.997e-6 http://gnomad.broadinstitute.org/variant/17-78092022-C-T
Variant2: NM_000152.4:c.2105G>T (p.Arg702Leu)
CAID: 92472 https://www.ncbi.nlm.nih.gov/clinvar/variation/92472/
gnomAD: Not in gnomAD
CaseAddInfo: Infantile Onset Pompe Disease
c.1942G > A(p.Gly648Ser)
Case34
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.
Variant: NM_000152.4:c.1942G>A (p.Gly648Ser)
ClinVar: 188902 https://www.ncbi.nlm.nih.gov/clinvar/variation/188902/
gnomAD: South Asian 3.365e-4, Overall 5.361e-5 http://gnomad.broadinstitute.org/variant/17-78086728-G-A
CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant
c.1796C > A(p.Ser599Tyr)
Case56
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.1796C>A (p.Ser599Tyr)
ClinVar: 551558 https://www.ncbi.nlm.nih.gov/clinvar/variation/551558/
gnomAD: European (Non-Finnish) 2.683e-5, Overall 1.207e-5 http://gnomad.broadinstitute.org/variant/17-78086418-C-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: Juvenile Late Onset Pompe Disease
c.784G > A(p.Glu262Lys)
Case85
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.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
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, 2 other patients have the same genotype
c.1978C > T(p.Arg660Cys)
Case10
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.1978C>T (p.Arg660Cys)
ClinVar: 558604 https://www.ncbi.nlm.nih.gov/clinvar/variation/558604/
gnomAD: East Asian 5.554e-5, Overall 4.142e-6 http://gnomad.broadinstitute.org/variant/17-78086764-C-T
Variant2: NM_000152.4:c.2221G>A (p.Asp741Asn)
ClinVar: 571521 https://www.ncbi.nlm.nih.gov/clinvar/variation/571521/
gnomAD: East Asian 1.087e-4, Overall 7.971e-6 http://gnomad.broadinstitute.org/variant/17-78090798-G-A
CaseAddInfo: Infantile Onset Pompe Disease
c.1411_1414del4(p.Glu471fs*5)
Case27
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.1411_1414delGAGA (p.Glu471fs*5)
ClinVar: 188874 https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/
gnomAD: East Asian 2.513e-4, Overall 1.781e-5 http://gnomad.broadinstitute.org/variant/17-78083827-CGAGA-C
Significance of this variant is unknown.
Variant2: NM_000152.4:c.460_465del (Arg154_Thre155del)
ClinVar: 551306 https://www.ncbi.nlm.nih.gov/clinvar/variation/551306/
gnomAD: Not in gnomAD
CaseAddInfo: Infantile Onset Pompe Disease
c.1143delC(p.Ala382Leufs*10)
Case58
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.1143delC (p.Ala382Leufs*10)
CAID: 370263 https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/
gnomAD: European (Non-Finnish) 8.946e-6, Overall 4.031e-6 http://gnomad.broadinstitute.org/variant/17-78082353-AC-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
c.1933G > A(p.Asp645Asn)
Case32
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.
Variant: NM_000152.4:c.1933G>A (p.Asp645Asn)
ClinVar: 188728 https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/
gnomAD: African 6.599e-5, Overall 8.250e-6 http://gnomad.broadinstitute.org/variant/17-78086719-G-A
CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant, 1 more patient has the same genotype
c.2560C > T(p.Arg854*)
Case21
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.1129G>C (p.Gly377Arg)
ClinVar: 497033 https://www.ncbi.nlm.nih.gov/clinvar/variation/497033/
gnomAD: European (Non-Finnish) 2.356e-5, Overall 1.072e-5 http://gnomad.broadinstitute.org/variant/17-78082341-G-C
CaseAddInfo: Infantile Onset Pompe Disease
10 mg/kg (N = 3)
Case4HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.1 pmol/punch/hr, 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.1441T>C (p.Trp481Arg)
ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/
gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C
CaseAddInfo:
20 mg/kg (N = 16)
Case17HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.38 umol/g/h, GAA activity at 12.7% 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.2242dupG (p.Glu748Glyfs)
ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/
gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG
CaseAddInfo:
20 mg/kg (N = 16)
Case8HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 8 pmol/punch/hr, 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.2242dupG (p.Glu748Glyfs)
ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/
gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG
CaseAddInfo:
5 mg/kg (N = 3)
Case2HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 6 pmol/punch/hr, GAA activity at 25% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
20 mg/kg (N = 16)
Case14HPOsFreeText: 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.1441T>C (p.Trp481Arg)
ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/
gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C
CaseAddInfo:
PD07
Patient7: Female, Southern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1432G>A (p.Gly478Arg)
ClinVar: 551295, https://www.ncbi.nlm.nih.gov/clinvar/variation/551295/
gnomAD: 8.525e-06, http://exac.broadinstitute.org/variant/17-78083849-G-A
Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)
ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/
gnomAD: n/a
PD04
Patient4: Female, southern 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.2185delC (p.Leu729Trpfs) **this is not the same protein transcript listed in paper (p.Thr729fsX8) but I could not find this in clinvar or allele registry)
ClinVar: 370552, https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/
gnomAD: n/a
31
Case31: Female, 15 yr diagnosis, 15.9 yr report
HPOsFreeText: FVC z-score sitting 1.33 (116% pred), FVC z-score supine 1.2 (115% pred), 100% MRC Scale, 1040 CK U/l, 2.5 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
6
Case6: Male, 1 yr onset, 2 yr diagnosis, 8.2 yr report
CasePresentingHPOs: HP:0001371 (Contractures)
HPOsFreeText: Wheelchair partially used, FVC z-score sitting -3.47 (59% pred), FVC z-score supine -4.36 (48% pred), 79% MRC Scale, 3078 CK U/l, 4.5 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No respiratory support
14
Case14: Male, 7 yr onset, 10 yr diagnosis, 10.7 yr report
CasePresentingHPOs: HP:0002650 (Scoliosis)
HPOsFreeText: Wheelchair used, Respiratory support at night, FVC z-score sitting -2.22 (75% pred), 80% MRC Scale, 540 CK U/l, 8,9 GAA activity (nmol/h/mg)^h from cultured fibroblasts
17
Case17: Male, 13 yr onset, 14 yr diagnosis, 14.3 yr report
HPOsFreeText: FVC z-score sitting -1.68 (81% pred), FVC z-score supine -1.77 (80% pred), 95% MRC Scale, 2935 CK U/l, 6.2 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
10
Case10: Male, 2.5 yr onset, 3 yr diagnosis, 13 yr report
CasePresentingHPOs: HP:0001371 (Contractures)
HPOsFreeText: FVC z-score sitting -3.01 (66% pred), FVC z-score supine -4.09 (54% pred), 84% MRC Scale, 1960 CK U/l, 8.6 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
23
Case23: Female, 1 yr onset, 1.9 yr diagnosis, 12.5 yr report
CasePresentingHPOs: HP:0002650 (Scoliosis)
HPOsFreeText: Wheelchair used at 6 yr, Respiratory support used at 6 yr, 10% MRC Scale, 1381 CK U/l, Deficient GAA activity (nmol/h/mg)^h from cultured fibroblasts
13
Case13: 56yo
CasePresentingHPOs: HP:0003325, HP:0002093, HP:0004887, HP:0020038
HPOsFreeText: GAA = 6.3%, BMI = 22.5, nucleo-capsular and subcortical white matter lacunes
CaseNotHPOs:
NotHPOsFreeText: No cardiovascular risk
CaseAddInfo: 24yr disease duration, variants in trans
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.784G>A (p.Glu262Lys)
ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/
gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A
8
Patient8: Female
CasePresentingHPOs: HP:0004887, HP:0002194
HPOsFreeText: ERT dosage = 20 mg/kg/2 w, able to sit independently, reversal of HCM, CRIM positive
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: Symptom onset, diagnosis, and ERT at 4mo, ERT last for 54mo, ventilation required at 60 mo, died at 60mo
CasePMIDs: 14695532, 14972326
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)
ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/
gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C
10
Patient10: Male
CasePresentingHPOs: HP:0002194, HP:0001522
HPOsFreeText: ERT dosage = 40 mg/kg/w, HCM reversal, CRIM positive
CaseNotHPOs: HP:0004887
NotHPOsFreeText:
CaseAddInfo: Symptom onset at 3w, diagnosis at 3mo, ERT at 5mo, ERT lasted for 5mo, died at 12mo
CasePMIDs: 22644586, 14695532
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)
ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A
17
Patient17: Female
CasePresentingHPOs: HP:0004887, HP:0003819
HPOsFreeText: ERT dosage = 20mg/kg/2w, able to sit, CRIM positive
CaseNotHPOs:
NotHPOsFreeText: no HCM reversal
CaseAddInfo: Symptom onset at 3mo, diagnosis at 6mo, ERT at 10mo, ERT lasted for 6mo, required ventilation at 26mo, died at 28mo
CasePMIDs: 22644586, 14695532
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)
ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A
5
Patient5: Female
CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522
HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: Symptom onset at 2mo, diagnosis and ERT at 4mo, ERT lasted for 1mo, ventilation required at 3mo, died at 5mo, variants in trans
CasePMIDs: 21763167, 11738358
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)
ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/
gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A
Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)
ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/
gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/17-78086424-C-T
13
Patient13: Female
CasePresentingHPOs:
HPOsFreeText: ERT dosage = 20mg/kg/2w, HCM reversal, CRIM positive, able to run and climb stairs, can speak well
CaseNotHPOs: HP:0004887, HP:0009046
NotHPOsFreeText:
CaseAddInfo: Symptom onset at 2mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 111mo, currently 10yo
CasePMIDs: 14695532, 14972326
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)
ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/
gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C
12/M
Patient 12: male
CasePresentingHPOs:
HPOsFreeText: CRIM positive, infusion associated reaction, heart normalization
CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0002546, HP:0000365, HP:0001371
CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 3yo, ERT at 4yo
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)
ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/
gnomAD: n/a
Variant2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)
ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/
gnomAD: 1.663e-05, http://exac.broadinstitute.org/variant/17-78085800-T-C
8/F
Patient8: Female
CasePresentingHPOs: HP:0004887, HP:0001270
HPOsFreeText: CRIM positive, tracheostomy partial heart normalization
CaseNotHPOs: HP:0025156, HP:0001371
NotHPOsFreeText: infusion associated reaction
CaseAddInfo: variants in trans, symptom onset at 1yo, diagnosis at 9yo, ERT at 10yo. Died due to infusion reaction with ERT.
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: 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
Variant2: NM_000152.4(GAA):c.670C>T (p.Arg224Trp)
ClinVar: 189188, https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/
gnomAD: 2.53e-05, http://exac.broadinstitute.org/variant/17-78079671-C-T
18/M
Patient18: Male
CasePresentingHPOs: HP:0004887, HP:0001270, HP:0002546
HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, heart normalization
CaseNotHPOs: HP:0025156, HP:0000365, HP:0001371
NotHPOsFreeText: infusion associated reaction
CaseAddInfo: homozygous variants in trans, symptom onset at 1yo, diagnosis at 1.5yo, ERT at 4yo
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)
ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/
gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A
5/F
Patient5: female
CasePresentingHPOs: HP:0001270
HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:25.600, infusion associated reaction, heat normalization
CaseNotHPOs: HP:0004887, HP:0025156, HP:0001371
CaseAddInfo: homozygous variants in trans, symptom onset and diagnosis at 1yo, ERT at 2yo. Died due to infusion reaction with ERT.
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)
ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/
gnomAD: n/a
13/F
Patient13: female
CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365
HPOsFreeText: CRIM positive, tracheostomy, partial heart normalization
CaseNotHPOs: HP:0001371
NotHPOsFreeText: infusion associated reaction
CaseAddInfo: variants in trans, symptom onset at 6yo, diagnosis and ERT at 11yo
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)
ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/
gnomAD: n/a
Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)
ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/
gnomAD: 5.884e-05, http://exac.broadinstitute.org/variant/17-78086713-G-A
22
Patient22: Male, 30 years report, 23 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 1.1% from leukocyte, Wheelchair needed
CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: Respiratory Assistance not needed
CaseAddInfo: LOPD
28
Patient28: Male, 70 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 6.7% from leukocyte, Respiratory Assistance needed
CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: Wheelchair not needed
CaseAddInfo: LOPD
16
Patient16: Female, 36 years report, 28 years onset
CasePresentingHPOs: HP:0001324 (Muscle weakness)
HPOsFreeText: GAA activity 1% from a dried blood spot
CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
32
Patient32: Female, 19 years onset
CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098, HP:0002240, HP:0002910 (Cardiomegaly, Muscle weakness, Respiratory distress, Hepatomegaly, Abnormal liver function)
HPOsFreeText: Wheelchair needed, Respiratory Assistance needed
CaseAddInfo: LOPD
10
Patient10: Male, 39 years report, 17 years onset
CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098, HP:0002240 (Cardiomegaly, Muscle weakness, Respiratory distress, Hepatomegaly)
HPOsFreeText: GAA activity 9.3% from leukocyte, Wheelchair needed, Respiratory Assistance needed
CaseAddInfo: LOPD
P8a
Patient8: Female, 61yo
CasePresentingHPOs: HP:0000822, HP:0003077
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 5yr follow-up MRI, 21yr disease duration, ERT lasted for 63mo
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.1478C>T (p.Pro493Leu)
ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/
gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T
P5a
Patient5: Male, 52yo
CasePresentingHPOs: HP:0003077, HP:0000822
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 15yr disease duration, ERT lasted for 63mo, 5yr follow-up MRI
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.1478C>T (p.Pro493Leu)
ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/
gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T
P17
Patient17: Male, 81yo
CasePresentingHPOs: HP:0003077, HP:0000822
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 6yr disease duration, ERT lasted 37mo
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.925G>A (p.Gly309Arg)
ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/
gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A
P9
Patient9: Male, 64yo
CasePresentingHPOs: HP:0000822, HP:0000819, HP:0001513
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 11yr disease duration, ERT lasted 14mo
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.925G>A (p.Gly309Arg)
ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/
gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A
P10a
Patient10: Female, 75yo
CasePresentingHPOs: HP:0000822
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 5yr follow-up MRI, 40yr disease duration, ERT lasted 103mo
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: NC_000017.11:g.(?80118193)(80118357_?)del (del exon 18)
ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/
gnomAD: n/a
6
Patient6: Male, 36yo at diagnosis, 40yo at ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 1.2 (2-10)
CaseNotHPOs:
NotHPOsFreeText: NIV and mobility aid not used
CaseAddInfo: 11yr disease duration
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)
ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/
gnomAD: n/a
15
Patient15: Female, 48yo at diagnosis and ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.48 (3-20), NIV required only after ERT
CaseNotHPOs:
NotHPOsFreeText: mobility aid not required
CaseAddInfo: 33yr disease duration
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)
ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/
gnomAD: n/a
21
Patient21: Male, 56yo at diagnosis and ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.57 (2-10), NIV and mobility aid required before and after ERT, developed wheelchair dependence after ERT
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 35yr 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_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs)
ClinVar: 189041, https://www.ncbi.nlm.nih.gov/clinvar/variation/189041/
gnomAD: n/a
22a
Patient22: Female, 40yo at diagnosis and ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:12,800, enzyme = 2.77 pmol/punch/h (7.3–39), NIV and mobility aid required before and after ERT
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 18yr disease duration, patient discontinued ERT, 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_000152.4(GAA):c.258dupC (p.Asn87Glnfs)
ClinVar: 282842, https://www.ncbi.nlm.nih.gov/clinvar/variation/282842/
gnomAD: 2.653e-05, http://exac.broadinstitute.org/variant/17-78078636-T-TC
4
Patient 4: Male, 37yo at diagnosis, 41yo at ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 2.1 (3-20), mobility aid required before and after ERT
CaseNotHPOs:
NotHPOsFreeText: NIV not used
CaseAddInfo: 10yr disease duration
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)
ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/
gnomAD: n/a
17
Patient17: Male, 34yo at diagnosis and ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:800, enzyme (μmol/g/h) = 0.75 (3-20), NIV required only after ERT began
CaseNotHPOs:
NotHPOsFreeText: mobility aid not required
CaseAddInfo: 17yr 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_001079803.2(GAA):c.896T>C (p.Leu299Pro)
ClinVar: 180144, https://www.ncbi.nlm.nih.gov/clinvar/variation/180144/
gnomAD: n/a
Detailed characteristics of these patients
Patient13: male, 32yo, juvenile onset
CasePresentingHPOs:
HPOsFreeText: LOPD, BMI = 24.9 / 25 / n-a, WGMS = 3 / 3 / n-a
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: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481+102_2646+31del)
ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/
gnomAD: n/a
3
Case#: 3, age 48, age 41 (report)
DiseaseAssertion: Pompe Disease
FamilyInfo: Family 3, no further information
CasePresenting HPOs:HP:0012378, HP:0003546, HP:0001324 (fatigue, exercise intolerance, muscle weakness)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: single gene sequencing/analysis, 63.85 NaG/AaGIA, 91% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range
Variants:
Variant 1:NM_000152.5(GAA):c.-32-3C>A
ClinVar: 371622
Variant 2:NM_000152.5(GAA):c.-32-3C>A
ClinVar: 371622
ParentalGenotypes: N/A
PreviouslyPublished: N/A
4
Case#: 4, age 24, age 18 (report)
DiseaseAssertion: Pompe Disease
FamilyInfo: Family 4, no further information
CasePresenting HPOs:HP:0012378, HP:0003546, HP:0001324 (fatigue, exercise intolerance, muscle weakness)
CaseHPOFreeText: vacuolar myopathy biopsy PAS +
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: single gene sequencing/analysis, 40.54 NaG/AaGIA, 90.54% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range
Variants:
Variant 1:NM_000152.5(GAA):c.2608C>T (p.Arg870Ter)
ClinVar: 189009
Variant 2: not reported
ParentalGenotypes: N/A
PreviouslyPublished: N/A
2/a
Case#: 2/a, age 20, age 14 (report)
DiseaseAssertion: Pompe Disease
FamilyInfo: Family 2, no further information
CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)
CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: single gene sequencing/analysis, 64.47 NaG/AaGIA, 92.28% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range
Variants:
Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)
ClinVar: 932904
Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)
ClinVar: 279811
ParentalGenotypes: N/A
PreviouslyPublished: N/A
b
CaseB: 40 years onset
CaseAddInfo: Late-Onset Pompe Disease
#17
Case17: Male, 11 years onset, 15 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
15
Case15: Female, 39 years onset, 40 years diagnosis, Italy
HPOsFreeText: See Group Phenotypes, ERT started at 41, GAA Activity at ~6.5 pmol/min/mg before ERT and ~11 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.2237G>A (p.Trp746Ter)
ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A
CaseAddInfo: Late Onset Pompe Disease
18
Case18: Female, Unknown years onset, Unknown years diagnosis, 25 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
11
Case11: Male, 24 years onset, 58 years diagnosis, 62 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Scapula alata)
CaseAddInfo: Late-Onset Pompe Disease
For GAA (Pompe disease) screening
CaseP1-GAA: Male, ethnicity = North African, country origin = Morocco
CasePresentingHPOs: HP:0010899, HP:0010916, HP:0003236
HPOsFreeText: enzyme activity = 0.61, CPK = 448 U/L, ALT = 48 U/L, AST = 98 U/L, CRIM positive
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: heterozygote, variants in trans. Patient underwent ERT.
CasePreviousTesting: initial and confirmatory DBS, biochemical tests, echocardiography
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
Variant2: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)
ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/
gnomAD: n/a
1/F
Patient1: Female, Caucasian, 10yo
CasePresentingHPOs:
HPOsFreeText: IOPD, rhGAA IgG antibody titer = 400, CRIM positive
CaseNotHPOs:
NotHPOsFreeText: no infusion associated reactions
CaseAddInfo: homozygous, 6.5mo at diagnosis, 7.0mo at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)
ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: 0.00001809, https://gnomad.broadinstitute.org/variant/17-78079656-G-A
9
Case#: Patient 9, Gender N/A, Onset at 3-4 months. Death around 1-2 years, Southeast Asian
DiseaseAssertion: Pompe disease
FamilyInfo: N/A
CasePresentingHPOs: HP:0001252, HP:0001270, HP:0001640, HP:0005165
Muscular hypotonia, Motor delay, Cardiomegaly, Shortened PR interval)
CaseHPOFreeText: BVH, Ejection fraction 10%, Creatine kinase levels 1,010u/l
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: No GAA measurement . Ejection fraction 10%, Creatine kinase levels 1,010u/l
PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions
Variant: NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)
ClinVar: 550327
CAID: N/A
gnomAD: Highes population MAF = 0.0001427 (Others)
ParentalGenotype: Both parents were carriers for the viariant c.1941C>G (p.Cys647Trp)
PreviouslyPublished: N/A
5
Patient5:
CasePresentingHPOs:
HPOsFreeText: Juvenile onset Pompe
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: homozygous
CasePMIDs:
CasePreviousTesting:
CaseGenotypingMethod: method not described
Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)
ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/
gnomAD: 0.000007972, https://gnomad.broadinstitute.org/variant/17-78082197-T-C
(Supplementary Table S3 shows details, IgG trajectories, and outcomes).
Patient 15 - IOPD - homozygous
Variant: NM_000152.4(GAA):c.925G>A (p.Gly309Arg)
ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/
gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A
P2
PatientF3P2: Female, 36 years diagnosis, European and Native American
CasePresentingHPOs: HP:0003236, HP:0012378, HP:0003547, HP:0009113, HP:0002910 (Increased serum CK, Fatigue, Shoulder weakness, Weak diaphragm, Increased transaminases)
HPOsFreeText: Decline in energy and strength reported with each of her four pregnancies most prominent after her youngest daughter's diagnosis of IOPD, Subsequent enzyme assay indicated deficient GAA activity via a dried blood spot (2.2 pmol/punch/hr, control >3.88 pmol/punch/hr), Pulmonary functioning tests (PFTs) showed a decrease in forced vital capacity (FVC) from 93% predicted seated to 72% predicted supine, Laboratory results demonstrated an elevated CK level of 490 U/L (control 30–220 U/L) and mild elevation of transaminases with AST of 83 U/L (control 15–41 U/L) and ALT of 60 U/L (control 14–54 U/L)
CaseAddInfo: Mother of proband F3P1, found to have minimally symptomatic LOPD
4-year-old Japanese girl
Case1: Female, 4 years old, Japanese
DiseaseAssertion: Thrombocytopenia
FamilyInfo: 4-generation pedigree available
ParentalGenotype: See Figure 1 A for parents in the pedigree
CasePresentingHPOs: HP:0004406, HP:0000979
(Recurrent epistaxis, purpura)
CaseHPOFreeText: Mild bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed reduced expression levels
PlateletAggregation: Platelet aggregation induced by ADP and collagen was markedly reduced but agglutination induced by ristocetin was within the normal range.
CasePreviousTesting: Direct sequencing analysis around T2231 in exon 14 of the ITGB3 gene. Genomic DNA extracted from the affected and unaffected individuals of the pedigree were amplified by PCR and sequenced (See Figure 2)
Gene: ITGB3
Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)
LegacyVariant: p.Leu718Pro
ClinVar: 50229
CAiD: CA143712
gnomAD: N/A
The patient is a Caucasian 43-year old female
Case1: Female, 43 years old, Caucasian
DiseaseAssertion: Thrombasthenia
FamilyInfo: Pedigree found in Fig. 2B
ParentalGenotype: See Pedigree Fig 2B
CasePresentingHPOs: HP:0000132 (Menorrhagia)
CaseHPOFreeText: Severe and frequent mucocutaneous hemorrhages, intra-peritoneal bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 25% decrease of GPIbα and a reduced mean value of side scatter in the patient’s platelets.
PlateletAggregation: Platelet aggregation was markedly reduced in response to ADP, epinephrine, collagen, and arachidonic acid but agglutination induced by ristocetin was normal
CasePreviousTesting: Screening for mutations was carried out by direct sequencing of PCR-amplified overlapping fragments of reversed transcribed αIIb and β3 mRNA.
Gene: ITGB3
Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)
LegacyVariant: (p.Leu718Pro)
ClinVar: 50229
CAiD: CA143712
gnomAD: N/A
Case#: Downes_2019_BSS, male, age unknown, South-Asian ancestry reported
DiseaseAssertion: BSS
FamilyInfo: NR
ParentalGenotype: NR
CasePresentingHPOs: NR
PlateletAggregation: NR
CaseHPOFreeText: NR
CaseNotHPOs:
CaseNotHPOFreeText:
ProteinExpression: NR
CasePreviousTesting:
GenotypingMethod: HTS panel described in supplementary table 3
PreviouslyPublished:
Gene: ITGA2B
Variant: homozygous c.1005_1013del (p.His335_Leu338delinsGln)
HGVS: NM_000419.5(ITGA2B):c.1005_1013del
ClinVarID: 626948
CAID:
gnomAD: not found in v.2.1.1
MultipleGeneVariants:
Adult woman/France
Case5: Woman (adult), age not specified, France
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Variant GT; therefore, 50% expression alphaIIbbeta3 (See Table 4)
Platelet Aggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2227_2229CTC (p.Leu744del)
LegacyVariant: (p.Leu718del)
ClinVar: 627279
CAiD: CA915940812
gnomAD N/A
PreviouslyPublished: PMID: 29296966
dentification of ACO2 variants in individuals with ION Cohorts including about 1000 molecularly undiagnosed ION individuals from France, Germany, Italy, Spain, Belgium and the UK were screened by targeted sequencing for the presence of ACO2 variants. Among individuals with a single ACO2 variant, we selected cases with an MAF lower than 0.0001, whereas in individuals with biallelic heterozygous composite or homozygous variants, we selected the cases with an MAF lower than 0.005 for each variant. This led to the identification of 50 individuals harbouring 1 of 43 different heterozygous mutations, among which 29 were novel, as well as 11 individuals with biallelic mutations, among which 8 were novel. A compilation of these variants and the associated amino acid changes are displayed on ACO2 primary sequence and 3D structure in Fig. 1A and C and listed in the Supplementary Table 1. Notably, four dominant variants p.(Arg474Gly), p.(Trp603Ser), p.(Ser669Leu) and p.(Arg671Trp) were identified in two unrelated individuals and p.(Arg671Gln) in four unrelated individuals, while one recessive variant, p.(Leu74Val), with an MAF value of 0.00369, was found in five unrelated ROA individuals, and also formerly described in eight individuals with syndromic ACO2 presentations. This p.(Leu74Val) variant was associated once with p.(Gly661Arg) in the P56 individual, a combination already reported in an ROA family.6 Segregation analysis was performed where available. In DOA cases, all affected relatives carried the variant, whereas some relatives in the families of patients P6, P8, P9, P13 and P33 carrying the variant were asymptomatic, as occasionally observed in families with OPA1 mutations.15,41 Moreover, segregation analysis revealed de novo mutations in the P15 and P18 index cases. Analysis of the types of mutations identified in ACO2 (Fig. 1B) revealed that two-third of all variants were missense mutations, irrespective of the dominant or recessive mode of inheritance, while nonsense, frame-shift, splice-site mutations and deletions accounted together for the third part of all mutations identified, without significant difference between the distribution of the mutation types between dominant and recessive cases (P-value: 0.80). Notably, the identification of null alleles in dominant cases suggests that ACO2 haploinsufficiency contributes mainly to DOA pathophysiology.
Case: Charif Patient #60, 7yo at report, 6yo at dx, male, European
CasePresentingHPOs:
CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.25, OS:0.08; central scotoma; ODS: temporal atrophy
CaseNOTHPOs:
CaseNOTHPOSFreeText: other symptoms
CasePreviousTesting:
CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing
Variant: NM_001098.2 c.525+1G>A; c.220C>G p.(Leu74Val) compound heterozygous
ClinVarID: or CAID: 1470169
AddCaseInfo: no segregation data
PreviouslyPublished: n/a
VariantEvidence: n/a
Identification of ACO2 variants in individuals with ION Cohorts including about 1000 molecularly undiagnosed ION individuals from France, Germany, Italy, Spain, Belgium and the UK were screened by targeted sequencing for the presence of ACO2 variants. Among individuals with a single ACO2 variant, we selected cases with an MAF lower than 0.0001, whereas in individuals with biallelic heterozygous composite or homozygous variants, we selected the cases with an MAF lower than 0.005 for each variant. This led to the identification of 50 individuals harbouring 1 of 43 different heterozygous mutations, among which 29 were novel, as well as 11 individuals with biallelic mutations, among which 8 were novel. A compilation of these variants and the associated amino acid changes are displayed on ACO2 primary sequence and 3D structure in Fig. 1A and C and listed in the Supplementary Table 1. Notably, four dominant variants p.(Arg474Gly), p.(Trp603Ser), p.(Ser669Leu) and p.(Arg671Trp) were identified in two unrelated individuals and p.(Arg671Gln) in four unrelated individuals, while one recessive variant, p.(Leu74Val), with an MAF value of 0.00369, was found in five unrelated ROA individuals, and also formerly described in eight individuals with syndromic ACO2 presentations. This p.(Leu74Val) variant was associated once with p.(Gly661Arg) in the P56 individual, a combination already reported in an ROA family.6 Segregation analysis was performed where available. In DOA cases, all affected relatives carried the variant, whereas some relatives in the families of patients P6, P8, P9, P13 and P33 carrying the variant were asymptomatic, as occasionally observed in families with OPA1 mutations.15,41 Moreover, segregation analysis revealed de novo mutations in the P15 and P18 index cases. Analysis of the types of mutations identified in ACO2 (Fig. 1B) revealed that two-third of all variants were missense mutations, irrespective of the dominant or recessive mode of inheritance, while nonsense, frame-shift, splice-site mutations and deletions accounted together for the third part of all mutations identified, without significant difference between the distribution of the mutation types between dominant and recessive cases (P-value: 0.80). Notably, the identification of null alleles in dominant cases suggests that ACO2 haploinsufficiency contributes mainly to DOA pathophysiology.
Case: Charif Patient #1, 25yo at report, female, European
CasePresentingHPOs:
CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.5, OS:0.63; ODS: diffuse loss;
CaseNOTHPOs:
CaseNOTHPOSFreeText: other symptoms
CasePreviousTesting:
CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing
Variant: NM_001098.2 c.172C>T p.(Arg58*) heterozygous
ClinVarID: or CAID: 441075
AddCaseInfo: no segregation data
PreviouslyPublished: n/a
VariantEvidence: n/a
KMP 15
Case#: KMP 15, female, 82 yrs, East Slovakia
DiseaseAssertion: HCM
FamilyInfo: yes
CasePresentingHPOs: n/a
CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 60%; NYHA III.; ICD yes; ECG; echocardiography;
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene
CaseGenotypingMethod: Sanger sequencing;
Variant: NM_000257.4(MYH7):c.2734A>G (p.Lys912Glu)
ClinVar: 520267 https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/
CAID: n/a
gnomAD: absent
Case#: Consequence 7 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.1608G>T (p.Glu536Asp)
ClinVar: 177671 https://www.ncbi.nlm.nih.gov/clinvar/variation/177671/
CAID: n/a
gnomAD: absent
Case#: Consequence 16 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)
ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/
CAID: n/a
gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T
Case#: Consequence 5 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.2198G>T (p.Gly733Val)
ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/
CAID: n/a
gnomAD: absent
Case#: Consequence 8 Table 1 in Data Supplement (1 cases)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)
ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/
CAID: n/a
gnomAD: absent
Case#: Consequence 2 Table 1 in Data Supplement (1 case)
DiseaseAssertion: HCM
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3
CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing
Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)
ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/
CAID: n/a
gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T
Q380RR628PA8, A20, L14Mild, survival beyond age 35, no mental retardation
Case#: Patient #17, Brazilian
DiseaseAssertion: MPS1, mild
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: survival beyond age 35
CaseNotHPOs:
CaseNotHPOFreeText: mental retardation
GenotypingMethod:
PreviouslyPublished:
Variant: Q380R; R628P (also A8, A20, L14)
ClinVar: 1064675
CAID:
SupplementalData:
4
Case4: Male, 45 years report, 44 years diagnosis, Germany
CasePresentingHPOs:
HPOsFreeText: 6-min walk test at 510 (m)
CaseNotHPOs: HP:0002878 (Respiratory failure)
NotHPOsFreeText: Not wheelchair bound
CaseAddInfo: 0 years on ERT
3
Case3: Male, 27 years report, 20 years diagnosis, Germany
CasePresentingHPOs: HP:0002878 (Respiratory failure)
HPOsFreeText: 6-min walk test at 201 (m)
CaseNotHPOs:
NotHPOsFreeText: Not wheelchair bound
CaseAddInfo: 7 years on ERT
The differential diagnosis of neurodegenerative disorders with atrophy of the cerebral and cerebellar cortex and cerebellar vermis is broad even in young age groups; concomitant occurrence of degeneration of the retina points to lysosomal storage disorders, mitochondrial disorders, defects of carbohydrate glycosylation, and infantile neuroaxonal dystrophy.1–4 We hereby report on the identification of a tricarboxylic acid (TCA) cycle defect manifesting in infancy by the degeneration of the cerebrum, cerebellum, and retina. The subjects of this study were eight individuals, two males and six females, originating from two unrelated families of Arab Muslim origin (Figure 1). Their clinical data are summarized in Table 1. All were born following an uneventful pregnancy and delivery and had normal birth weights, head circumferences, and Apgar scores. Symptoms were first noted at 2–6 months of age and included variable appearance of truncal hyptonia, head bobbing, athetosis, generalized seizures, and ophthalmologic abnormalities that included strabismus, nystagmus, abnormal eye movements, and abnormal pursuit. The course was characterized by failure to thrive, gradual evolution of severe muscle wasting despite satisfactory oral intake, worsening of the hypotonia, attenuating deep tendon reflexes until complete areflexia was reached, progressive microcephaly, variable forms of seizures that were typically triggered by intercurrent febrile illnesses and were partly responsive to anticonvulsants, and failure to gain developmental milestones, culminating in profound psychomotor retardation. A distinctive feature was the appearance of head bobbing and athetoid movements of the upper limbs along with horizontal nystagmus when the individuals were held at the upright position. Visual tracking, normal at the newborn period, steadily deteriorated with the gradual evolution of bilateral optic atrophy. Visual evoked potentials in early infancy were normal, but the electroretinogram responses became critically reduced over the first two years of life, indicating severe retinal dystrophy. Similarly, auditory brain responses declined steadily, reflecting sensorineural hearing loss of variable severity. EEG disclosed generalized or focal spike and wave activity and slow background compatible with nonspecific encephalopathy. Electrophysiologic assessment of peripheral muscles and nerves performed in individual V-2 at 2 years revealed a normal electromyogram and a mild decrease of peripheral sensory and motor velocity suggesting demyelination. Taken together with the gradual disappearance of tendon reflexes, this finding indicates an evolving peripheral demyelinating neuropathy. Figure 1. Open in a new tab Pedigrees of the Two Families (A) Family A and (B) Family B. Affected individuals are represented by filled symbols.Table 1. Clinical Features of Affected Individuals Family A Family B IV-3 IV-5 V-2 V-5 V-7 III-1 III-2 III-3 Sex m f f f m f f f Current age (years) 18 13 7 3 0.5 9 8 2 Birth weight (centile) 2,900 g (10) 3,700 g (75) 2,700 g (10) 2,800 g (15) 3,700 g (75) 3,220 g (25) 3,450 g (50) 2,750 g (10) Birth head circumference (centile) 35 cm (40) 35 cm (50) 35 cm (50) 34 cm (25) 35 cm (40) 34.5 cm (40) 35 cm (50) 34 cm (25) Initial manifestations (age at presentation) H, A (5 months) H, A (6 months) H, A (2 months) H, E (4 months) H, E (3 months) H, S (3 months) A, H (5 months) A, E (5 months) Current weight (centile) 25 kg (−5 SD) 26 kg (−4 SD) 11 kg (−5 SD) 9 kg (−4 SD) 7.7 kg (25) 13 kg (−6 SD) 12 kg (−6 SD) 8 kg (−4 SD) Current head circumference (centile) 47 cm (−5 SD) 49.5 cm (−3 SD) 46.5 cm (−3.5 SD) 46.5 cm (5) 42.7 cm (25) 48.5 cm (−2.5 SD) 48 cm (3) 45.5 cm (5) Global DD/MR profound severe profound profound moderate profound profound severe Current motor skills no intentional movements crawls, rolls sits with support does not roll rolls, does not sit lift head when supine does not role does not role roles both sides Current cognitive skills vegetative state, no smile smile, recognize family smile, recognize family smile, recognize family smile, recognize family no eye contact, does not recognize family no eye contact, responds to auditory stimuli smile, recognize family Ataxia yes yes yes yes very mild yes yes yes Seizures generalized generalized focal and generalized focal and generalized no generalized myoclonic and focal focal and generalized no Retinal dystrophy (age at diagnosis) not evaluated severe (4 years) severe (1 year) severe (1 year) not evaluated profound (2 years) profound (1.5 years) moderate (1.5 years) ophthalmology optic atrophy, strabismus optic atrophy, strabismus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus strabismus optic atrophy, nystagmus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus Initial MR scan (age) not done normal (11 months) mild CoA (3 months) mild CoA (frontal and temporal) (11 months) normal (in utero, 30 weeks) CoA (frontal and temporal) mild thinning of CC (7 months) CoA abnormal WM (16 months) normal (in utero, 31 weeks) Last MR scan (age) not done severe CeA, moderate CoA (frontal and temporal), abnormal periventricular WM signal (12 years) severe CeA, moderate CoA (frontal and temporal), thin CC abnormal WM signal (4 years) severe CeA, moderate CoA (frontal and temporal), thin CC, abnormal WM signal (2.5 years) not done not done mild CoA and CeA (1y) Tendon reflexes absent brisk absent absent normal absent decreased absent Other severe scoliosis moderate SNHL severe SNHL (hearing aids) Open in a new tab The following abbreviations are used: A, ataxia/athetoid movements; H, hypotonia; E, eye abnormalities; S, seizures; HC, head circumference; DD, developmental delay; MR, mental retardation; CoA, cortical atrophy; CeA, cerebellar atrophy; WM, white matter; CC, corpus callosum; SNHL, sensorineural hearing loss.During gestation and throughout the first 6 months, brain MRI was typically normal. Thereafter, repeated MR scans (Figure 2) displayed progressive cerebellar atrophy of both hemispheres and the vermis. In addition, symmetric cortical atrophy gradually evolved, affecting mainly the frontal and temporal lobes along with a striking thinning of the corpus callosum. White matter abnormalities, indicated by T2 and fluid-attenuated inversion recovery (FLAIR) periventricular hyperintense signals, were first noted during the second year of life. Taken together, these serial MR scans revealed generalized progressive brain atrophy affecting primarily the cerebellum and to a lesser extent the white matter and the frontal and parietal lobes of the cerebral cortex. Figure 2. Open in a new tab Representative MRI Findings (A) T2-weighted, coronal section image of individual V-2 at 3 months shows a normal cerebellum and mild cortical atrophy. (B) T1-weighted, coronal section scan of the same individual at 4 years displays severe atrophy of the cerebellar hemispheres (arrowheads) and the vermis (arrows). (C) T1-weighted, coronal section image of individual IV-5 at 12 years shows enlarged cerebellar folia and reduced volume indicating generalized (vermian and hemispheral) atrophy. Note also the mild cortical atrophy and visible sulci. (D) Cortical atrophy and white matter abnormal signals (arrows) demonstrated by FLAIR image of coronal section in the same individual. (E) Moderate cortical atrophy, very thin corpus callosum (arrow), and cerebellar atrophy (arrowhead) in a T1-weighted, sagital section of individual V-5 at 2.5 years. (F) FLAIR image, axial section of individual V-5 displaying frontal and temporal cortical atrophy compared with relatively preserved occipital cortex. The abnormal periventricular white matter signal (arrow) is consistent with dysmyelination.
Case#: Spiegel Patient V-2 (proband not designated, so was chosen), female, 7yo at report, Arab Muslin origin
DiseaseAssertion: Infantile Cerebellar-Retinal Degeneration
FamilyInfo: All eight individuals were homozygous for the mutation; ten parents and one of the healthy sibs were heterozygous, and three healthy sibs were homozygous for the normal allele. 3 additional affected individuals are deceased, so it is possible that they were not genotyped and that may be the reason for the discrepancy in the count.
CasePresentingHPOs: HP:0000648, HP:0000639, HP:0012736, HP:0001252, HP:0001251, HP:0002194, HP:0100543, HP:0007359, HP:0002197, HP:0000556, HP:0002120, HP:0001272, HP:0033725, HP:0002500, HP:0001284, HP:0000407
CaseHPOFreeText: birth weight= 2,700 g (10th centile); birth head circumference= 35 cm (50th centile); initial manifestations: hypotonia and ataxia at 2 months; current weight= 11 kg (−5 SD); current head circumference= 46.5 cm (−3.5 SD); current motor skills= does not roll; current cognitive skills= smile, recognize family; focal and generalized seizures; severe retinal dystrophy dx at 1yo; mild cortical atrophy on MR scan at 3mo; severe cerebellar atrophy, moderate cortical atrophy (frontal and temporal), thin corpus callosum, abnormal white matter signal last MR scan at 4 yo; moderate sensorineural hearing loss
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: homozygosity mapping, WES
PreviouslyPublished: n/a
Variant: c.336C>G in ACO2 [MIM 100850] (NM_001098.2), which causes p.Ser112Arg (NP_001089.1). homozygous
ClinVar: 29584
FunctionalEvidence: Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded,
AdditionalInfo: 2 "unrelated" families reported, but "Affected individuals of both unrelated clans shared a similar homozygous haplotype, indicating that Ser112Arg is a founder mutation in this population" so will count the segregations as one family
SupplementalData: n/a
926T > C and 121–1G > A in one case
Case: Haagerup II:8
CasePresentingHPOs:
CasePresentingHPOsFreeText: not specified
CaseNOTHPOs:
CaseNOTHPOSFreeText: not specified
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variants: c926T>C and c121-1G>A
ClinVarID: or CAID: ClinVarID: 8426; ClinVarID: 859435
gnomAD: 2/129174 European (non-Finnish) alleles at a frequency of 0.00001548 with no homozygotes; 4/112000 European (non-Finnish) alleles at a frequency of 0.00003571 with no homozygotes
AddCaseInfo:
PreviouslyPublished: no
VariantEvidence: predicted but variant was proven to segregate with disease; predicted to delete all of exon 3
4H-Sc.236C>T (p.A79V)c.1882C>T (p.R628*)This report
Case#: Kwak Patient #4, 2yo at dx
DiseaseAssertion: Hurler-Scheie
FamilyInfo:
CasePresentingHPOs: HP:0000280, HP:0007957, HP:0100790, HP:0000924, HP:0001627, HP:0001433
CaseHPOFreeText: IDUA activity=6.5 nmol/mg protein/hr, uGAGs=202.8 CPC unit/g creatinine
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished:
Variant: c.236C>T (p.A79V); c.1882C>T (p.R628*)-Path in ClinVar
ClinVar: 1458769; 550421
CAID:
SupplementalData: supplemental file contains phenotype information
The ethnic background of these families was as follows: northern European (two), Czech, Spanish, Portuguese (two), Indian, and Honduran. Genomic DNA was extracted from blood leukocytes using the Puregene Genomic DNA Isolation kit (Gentra Systems, Minneapolis, Minnesota). Exons 2–8 of the cathepsin K gene (14) were amplified from genomic DNA of Pycno patients by PCR, isolated, and sequenced by cycle sequencing with an ABI 377 Sequencer (Perkin-Elmer Corp., Norwalk, Conneticut, USA).
Case: Family 2
CasePresentingHPOs:
CasePresentingHPOsFreeText: not specified
CaseNOTHPOs:
CaseNOTHPOSFreeText: not specified
CasePreviousTesting: none
CaseGenotypingMethod: Exons 2-8 were amplified by PCR and sequenced.
Variant: Q190X
ClinVarID: or CAID: ClinVarID: 371328
gnomAD: The variant is reported in 1/30616 South Asian alleles at a frequency of 0.00003266, with no homozygotes in gnomAD v2.1.1.
AddCaseInfo:
PreviouslyPublished:
VariantEvidence: none
Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene.
Sharkia Proband A-3, onset at 5 weeks old, 5yo at report, Caucasian, American, male. Patient A3 has
Variant: c.590A>G and c.172C>T
CaseHPO: HP:0001252, HP:0001251, HP:0001250, HP:0002120, HP:0001272, HP:0000648, HP:0000512, HP:0012736, HP:0001508, HP:0000252, HP:0030890
4 aged 10 (II‐1), 14 (II‐2), 43 (I‐4) and 46 years (I‐5),
Case#: 1. Patient II-4 43 years
DiseaseAssertion: Hypertrophic cardiomyopathy and left ventricular noncompaction
FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.
ParentalTesting: NR
CasePresentingHPOs: NR
CaseHPOFreeText: The patient had thickened heart muscle, abnormal heartbeats, and extra ridges and deep spaces in the heart muscle.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: ECG, heart monitoring, heart ultrasound, and genetic testing
Genotyping Method: Next- generation sequencing and sanger sequencing
FunctionalAnalysis: computer testing suggested the ACTC1 gene change could weaken the protein
Variant: NM_005159.4:c.62C>T
Clinvar: 410264
CAID: CA16614451
gnomAD: NR
AdditionalInfo: His heart pumping ability was 55%. This article reported changes in his heart muscle cells.
Case#: 2 Patient II-5 46 years old
DiseaseAssertion: HCM and LVNC
FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.
ParentalTesting: NR
CasePresentingHPOs: NR
CaseHPOFreeText: The patient had thickened and enlarged heart muscle, abnormal heartbeats, and deep spaces in his heart muscle. He als had temporary episodes of reduced blood flow to the brain.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart MRI, heart biopsy and genetic testing
Genotyping Method: NGS and sanger sequencing
FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.
Variant: NM_005159.4:c.62C>T
Clinvar: 410264
CAID: CA16614451
gnomAD: NR
AdditionalInfo: His heart pumping ability was 30%. He received a defibrillator and was considered for a heat transplant. He also had a second gene change in TTN.
Case#: 3 Patient II-1 10 years
DiseaseAssertion: left ventricular noncompaction
FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.
ParentalTesting: NR
CasePresentingHPOs: NR
CaseHPOFreeText: The patient had extra ridges and deep spaces in his heart muscle. His ECG also showed changes in his heart's electrical activity.
CaseNotHPOs: NR
CaseNotHPOFreeText: Normal heart muscle thickness and normal heart pumping ability.
CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart biopsy and genetic testing
Genotyping Method: NGS and sanger sequencing
FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.
Variant: NM_005159.4:c.62C>T
Clinvar: 410264
CAID: CA16614451
gnomAD: NR
AdditionalInfo: His heart pumping ability was 63%.He received medication and remained stable during follow up.
Case#: 4 Patient III-2 14 years
DiseaseAssertion: HCM and LVNC
FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.
ParentalTesting: NR
CasePresentingHPOs: NR
CaseHPOFreeText: The patient had thickened heart muscle extra ridges and deep spaces in his heart, and episodes of fast or abnormal hearbeats.
CaseNotHPOs: NR
CaseNotHPOFreeText: Heart MRI did not show sign of heart muscle scarring
CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart biopsy and genetic testing
Genotyping Method: NGS and sanger sequencing
FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.
Variant: NM_005159.4:c.62C>T
Clinvar: 410264
CAID: CA16614451
gnomAD: NR
AdditionalInfo: His heart pumping ability was 60%.He received medication and remained stable during follow up.
Left ventricular noncompacti
Case#: P16, 17 year old male
DiseaseAssertion: left ventricular noncompaction cardiomyopathy
FamilyInfo: His mother, sister, and grandfather on his mothers side also had LVNC
ParentalTesting: NR
CasePresentingHPOs: NR
CaseHPOFreeText: The patient had an abnormal structure in the left side of his heart. His heart ultrasound showed extra muscle ridges and deep spaces in the heart muscle.
CaseNotHPOs: NR
CaseNotHPOFreeText: The study did not report fainting, heart rhythm problems, blood clots, or heart failure for this patient.
CasePreviousTesting: Heart ultrasound, ECG, heart MRI, blood tests, and genetic testing.
Genotyping Method: Next generation sequencing followed by Sanger sequencing to confirm this gene change
FunctionalAnalysis: NR
Variant: NM_005159.5:c.329>T
Clinvar: 2137647
CAID: CA391631478
gnomAD: Exact frequency not provided
AdditionalInfo: The patient's heart pumping ability was 70 %on ultrasound. Researchers classified his ACTC1 variant as a variant of uncertain significance meaning they were not sure whether it causes diseases.
30-year-old c
Case#: 30 year old female athlete
DiseaseAssertion: Subclinical hypertrophic cardiomyopathy
FamilyInfo: Her mother has HCM and the same ACTC1 gene change. Her grandmother and uncle on her mothers side died suddenly.
ParentalTesting: Her mother tested positive for the ACTC1 gene change and there isn't any information about the father.
CasePresentingHPOs: NR
CaseHPOFreeText: The patient did not have dizziness, fainting, trouble breathing or chest pain. Her heart muscle was not thickened.
CaseNotHPOs: NR
CaseNotHPOFreeText: The patient sometimes felt her heart beating unusually during exercise. A heart MRI showed small changes in her heart muscle and heart valve.
CasePreviousTesting: The patient had an ECG, heart ultrasound, heart monitor and heart MRI
Genotyping Method:Sanger sequencing was used to test the ACTC1 gene.
FunctionalAnalysis: NR
Variant: ACTC1 p.Val11Leu
Clinvar: 2947021
CAID: CA391633409
gnomAD: NR
AdditionalInfo: The patient continued playing competitive sports and had regular heart checkups.
4 generations
Case#: Family 1, individual II-5
DiseaseAssertion: Dilated cardiomyopathy
FamilyInfo: The proband has a family history of DCM. His father and brother also had DCM and died from heart failure at ages 69 and 63 respectively. The disease follows an autosomal dominant inheritance pattern.
ParentalTesting: Want reported, his father had DMC but this article does not confirm genetic testing of his parents.
CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644) & left ventricular systolic dysfunction (HP:0005162)
CaseHPOFreeText: The proband was diagnosed with DCM at age 45 and received medication for heart failure. At the time of the study he was 66 years old. His echocardiogram showed an enlarged left ventricle and reduced heart function with an ejection fraction of 33%.
CaseNotHPOs: NR
CaseNotHPOFreeText: The researchers reported no other structural heart diseases or conditions contributing to DCM in the affected family members, including coronary heart disease, valvular heart disease, viral myocarditis and hypertension.
CasePreviousTesting: ECG, clinical examination and routine laboratory testing were part of the study assessment. The probands echocardiogram showed a left ventricular end diastolic diameter of 63 mm and an ejection fraction of 33%.
Genotyping Method: Genome wide microsatellite screening, genetic linkage analysis, whole exome sequencing and sanger sequencing.
FunctionalAnalysis: Laboratory experiments showed that the KLF13 E144X mutation reduced the proteins ability to activate the heart related genes ACTC1 and MYH7. The mutation also affected DNA binding cooperation with GATA4 and normal nuclear localization.
Variant: KLF13 c.430G >T
Clinvar: NR
CAID: CA391891162
gnomAD: The researchers reported that the variant was absent from gnomAD and other population databases at the time of their study. No numerical allele frequency was provided.
AdditionalInfo: The proband is a male from a 4th generation Chinese family. His KLF13 mutation was associated with familial DCM. the researchers found that the mutation was shared by affected family members and was absent from unaffected family members and 418 unrelated healthy controls.
amil
Case#: Family 2, III-10 47 year old female
DiseaseAssertion: Dilated cardiomyopathy
FamilyInfo: Multiple family members had DCM. The disease followed an autosomal dominant inheritance pattern.
ParentalTesting: NR
CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)
CaseHPOFreeText:Female aged 47 with DCM. Her left ventricular end diastolic diameter was 57mm and her ejection fraction was 40%.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: Echocardiogram and clinical cardiac evaluation.
Genotyping Method: Sanger sequencing of KLF13
FunctionalAnalysis: The E194X mutation reduced the ability of KLF13 to activate ACTC1 and MYH7 and bind their promoters. It also disrupted cooperation with GATA4.
Variant: KLF13 c.580G>T
Clinvar: NR
CAID: NR
gnomAD: The variant was reported as absent from gnomAD at the time of the study.
AdditionalInfo: The mutation was found in affected family members and was absent from 418 unrelated healthy controls.
Famil
Case#: Family 3, III-4
DiseaseAssertion: Dilated cardiomyopathy
FamilyInfo: The family had multiple cases of DCM consistent with autosomal dominant inheritance.
ParentalTesting: NR
CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)
CaseHPOFreeText: Female age 41 with DCM. her left ventricular end diastolic diameter was 58 mm and her ejection fraction was 43%.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: Echocardiogram and clinical cardiac evaluation
Genotyping Method: Sanger sequencing of KLF13
FunctionalAnalysis: The C199R mutation reduced KLF13 ability to activate ATC1 and MYH7 bind DNA and work together with GATA4.
Variant: KLF13 c.595T>C
Clinvar: NR
CAID: CA391512228
gnomAD: The variant was reported as absent from gnomAD at the time of the study.
AdditionalInfo: The variant was associated with familial aDCM and was not detected in the 418 healthy controls.
TTL Overexpression Rescues Hypertrophy in Cardiomyocytes Derived From an HCM hiPSC Line
Case1: HCM patient-derived cell line UKEi070-A (demographics not reported in this paper) DiseaseAssertion: HCM
ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Genotyping Method: Not reported in this paper; it references a previously established patient-derived cell line. FunctionalAnalysis: The variant is reported to cause MYBPC3 protein haploinsufficiency in cardiomyocytes. In this study, TTL overexpression normalized cell hypertrophy in the HCM cell model. Variant: NM_000256.3:c.2308G>A (heterozygous; the paper reports the splice consequence as p.Asp770Serfs98X) ClinVar: 36604 CAID: gnomAD: NR AdditionalInfo: The paper uses patient-derived induced pluripotent stem cell cardiomyocytes; it does not provide the patient’s age, sex, or pedigree.
A 50-year-old male with a prior clinical diagnosis of hypertrophic cardiomyopathy presented with monomorphic ventricular tachycardia.
Case1: 50 year old male DiseaseAssertion: HCM; hydroxychloroquine cardiotoxicity FamilyInfo: Six children undergoing predictive testing for the familial MYBPC3 variant; family history not reported ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: Monomorphic ventricular tachycardia, dyspnea, nausea, vomiting, biventricular hypertrophy, systolic dysfunction, cardiogenic shock CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Prior CMR showed nonobstructive HCM; cardiomyopathy gene panel identified the variant Genotyping Method: Cardiomyopathy gene panel FunctionalAnalysis: Altered splicing with exon 30 skipping; authors describe a nonfunctional protein or premature stop codon Variant: c.3330+5G>C ClinVar: 42706 CAID: gnomAD: 0.03% (as reported in the article) AdditionalInfo: Long-term hydroxychloroquine exposure for malaria prophylaxis; biopsy findings were consistent with both HCM and hydroxychloroquine cardiotoxicity
3.1.2 Patient 2—heart transplanted DCM and intronic MYBPC3 variant
Case2: 12-year-old boy (Patient 2) DiseaseAssertion: DCM FamilyInfo: Family history unremarkable. ParentalTesting: The MYBPC3 variant was inherited from his father. The father’s cardiac phenotype is not reported. CasePresentingHPOs: HP:0001644, HP:0003546 CaseHPOFreeText: Severely depressed biventricular function; heart transplantation for decompensated heart failure. CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Previous WES was negative; the variant’s intronic region was not adequately covered. Genotyping Method: Whole-genome sequencing (WGS; Illumina NovaSeq 6000; aligned to hg19/GRCh37). FunctionalAnalysis: SpliceAI predicted a potential splicing effect; no functional assay in this patient is reported. Variant: NM_000256.3:c.1224-80G>A (heterozygous intronic variant) ClinVar: 693982 CAID: CA221697326 gnomAD: 0.0000637 AdditionalInfo: The authors classified the variant as a VUS in this DCM case because evidence for a MYBPC3–DCM relationship is limited. ClinVar currently reports a pathogenic/likely pathogenic aggregate classification, primarily in relation to HCM. Reanalysis found no second MYBPC3 variant.
6
Case#: Family #6; 36-year-old male
DiseaseAssertion: Arrhythmogenic right ventricular cardiomyopathy (ARVC); diagnosed according to the 2010 revised Task Force Criteria
FamilyInfo: Family #6. No informative segregation evidence specifically linking the MYL3 variant to ARVC was reported. The authors noted that family screening was incomplete or normal in other families, but did not specify which circumstance applied to Family #6.
ParentalTesting: NR
CasePresentingHPOs: HP:0006682 (PVCs)
CaseHPOFreeText: Symptomatic presentation; major right ventricular structural abnormality; minor ECG repolarization criterion; 1,181 ventricular ectopic beats on Holter monitoring; sustained ventricular arrhythmia (specific rhythm not reported).
CaseNotHPOs: HP:0001279 (Syncope); HP:0005162 (Abnormal left ventricular function)
CaseNotHPOFreeText: No cardiac syncope or left ventricular dysfunction reported. Absence of cardiac syncope does not necessarily exclude every form of syncope.
CasePreviousTesting: No pathogenic or likely pathogenic variants identified in established ARVC-associated genes (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, PLN, SCN5A). Subsequent screening included nine sarcomere genes: ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1. The study used broad genetic testing, including whole-exome sequencing in a subset of probands; whether Family #6 underwent whole-exome sequencing was not specified.
Genotyping Method: Sarcomere-gene sequencing and deletion/duplication analysis through clinical cardiomyopathy panels, research-based next-generation sequencing panels, or whole-exome sequencing. The exact initial platform for Family #6 was not specified. Identified variants were confirmed by PCR amplification and Sanger sequencing.
FunctionalAnalysis: NR
Variant: MYL3 NM_000258.2:c.461G>A (p.Arg154His); missense variant; exon 4
ClinVar: 14062
CAID: CA013861
gnomAD: MYL3 c.461G>A (p.Arg154His), GRCh38: 3-46859495-C-T. gnomAD v4: Exome AF = 0.00003557; Genome AF = 0.00001971; Total AF = 0.00003408. European (non-Finnish): AC = 52, AF = 0.00004407. https://gnomad.broadinstitute.org/variant/3-46859495-C-T?dataset=gnomad_r4
AdditionalInfo: Murray et al. (2018), Tables 1 and 2, Family #6. The MYL3 variant was classified as likely pathogenic (LP) according to ACMG criteria, with a PolyPhen-2 score of 0.861. The proband met criteria for definite ARVC, with no reported left ventricular dysfunction. Although the variant was rare and computationally predicted to be damaging, the authors emphasized that evidence demonstrating a causal relationship between sarcomere variants and ARVC remained insufficient. No direct functional analysis of this variant was performed in the study.
The index patient
Case#: Female, 4 months, Swedish
DiseaseAssertion: dilated cardiomyopathy
FamilyInfo: Strong family history of DCM and faily history of SCD due to DCM. Maternal grandfather had enlarged left ventricle.
ParentalTesting:
CasePresentingHPOs: HP:0005162, HP:0031295, HP:0001653,
CaseHPOFreeText: enlarged left ventricle,
CaseNotHPOs:HP:0011947
CaseNotHPOFreeText: circulatory collapse
CasePreviousTesting: NR
Genotyping Method: Sanger sequencing
FunctionalAnalysis: NR
Variant: NM_001276345.2:c.548G>A
ClinVar:43649
CAID: CA004727
gnomAD:NR
AdditionalInfo: During cardiac catheterization, cardiac resuscitation due to circulatory collapse was needed.
proband with infantile hypertrophic cardiomyopathy
Case1: Male, Infant, Tunisian
DiseaseAssertion: infantile-onset HCM and mitral valve dysplasia
FamilyInfo: Family with consanguinity in which four children had died before one year of age. The father (37 years old) and mother (27 years old) of the proband are consanguineously related. Two infants (VI:1 and VI:2) died at less than 30 days of age from cardiorespiratory arrest, and two (VI:3 and VI:4, proband) of them displayed abnormal cardiac findings on chest roentgenogram. While all four children displayed hepatomegaly and general hypotonia, VI:3 and VI:4 had a marked increase in heart size and died from refractory cardiogenic shock. The status of the MYL2 allele in siblings is unknown. The proband (fs/fs) was homozygous for the MYL2-fs allele while the parents were found to be heterozygous (fs/wt) carriers. The father (37 years old) and mother (27 years old) of the proband are consanguineously related, were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram
ParentalTesting: Homozygous variant in the proband and that the parents are heterozygous carriers using Sanger DNA sequencing of the genomic region. Father (37 years old) and mother (27 years old) were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram
CasePresentingHPOs: HP:0200128, HP:0001653, HP:0002092, HP:0001639, HP:0002240
CaseHPOFreeText: Showed a rapid decline in health and was treated for various periods in neonatal intensive care units. The patient also displayed severe mitral valve regurgitation with abnormal thickening of the mitral valve leaflets and pulmonary arterial hypertension. Post-mortem examination of the proband’s heart confirmed severe biatrial dilatation, significant biventricular hypertrophy with small ventricular cavities and severe mitral valve dysplasia
CaseNotHPOs: NR
CaseNotHPOFreeText: no gross developmental defects
CasePreviousTesting: No prior genetic testing reported before exome sequencing
Genotyping Method: Performed exome sequencing on the proband. Exome libraries were constructed using the Agilent SureSelectQXT Target Enrichment System for Illumina Multiplexed Sequencing Protocol (Agilent Technologies, CA). DNA libraries were captured with the Agilent Clinical Research Exome Kit. Paired-end 150 base pair reads were generated for exome-enriched libraries sequenced on the Illumina HiSeq 4000 to a targeted depth of 100× coverage
FunctionalAnalysis: Functional analysis performed. Immunohistochemical analysis of MYL2 expression in the proband’s ventricular myocardium shows a remarkable reduction in the expression of MYL2 as compared to control. Also, MYL2 mRNA was detected in the ventricle of the proband by RT-PCR. This suggests that the frameshift variant adversely affects the levels of MYL2 protein in the proband. Using immunoblot analysis, we observed that overexpression of the MYL2-fs variant was significantly reduced compared to stop-gain variants and the missense variant. When the H9c2 cells were treated with MG-132 after transfection with the MYL2-fs construct, the GFP signal corresponding to MYL2-fs was recovered. The in vitro experiments indicate that the MYL2-fs variant is not stable and that proteasome-mediated degradation of the translated product plays a key role in the instability of the protein. The overexpression of the fs variant identified in our proband or the MYL2-G162R missense variant failed to rescue the phenotype. Results reported in Figures 2, 3, and 4.
Variant: NM_000432.3:c.431_432delCT
ClinVar: NR
CAID: UnregisteredVariant
gnomAD: NR
AdditionalInfo: 4 siblings who died before 1 year of age but MYL2 genotyping was only confirmed in the proband (VI:4)
A 37-year-old man
Case1: Male, 37 years old, Colombian
DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy
FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.
ParentalTesting: NR
CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315
CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: NR
Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation
FunctionalAnalysis: NR
Variant: NM_000432.3:c.260G>C
ClinVar: 43461
CAID: CA009968
gnomAD: NR
AdditionalInfo: NR
Genetic variant affecting the myosin light chain 2 related to familial hypertrophic cardiomyopathy
PMID: 33139982
Gene: MYL2
HGNC ID: 7583
the proband
Case#: Japanese female
DiseaseAssertion: Mild cardiac hypertrophy and asymmetric septal hypertrophy with myocardial hypertrophy increasing.
FamilyInfo: mother and grandmother showed phenotype. Probands mother has the Arg92Trp mutation of TNNT2.
ParentalTesting:not reported
CasePresentingHPOs: HP:0001670
CaseHPOFreeText: not reported
CaseNotHPOs:not reported
CaseNotHPOFreeText:not reported
CasePreviousTesting: DNA analysis
Genotyping Method: Patients with familial HCM
FunctionalAnalysis:not reported
Variant:NM_001276345.2:c.107A>T
ClinVar:not reported
CAID:CA344207376
gnomAD:not reported
AdditionalInfo: pedigree and phenotype associated with Family C.
The baby was born
Case#: Female, 6 months
DiseaseAssertion: Dilated cardiomyopathy
FamilyInfo: Mother was age 40 at time of birth, which is a high-risk factor for birth defects
ParentalTesting:
CasePresentingHPOs: HP:0031664, HP:0010438, HP:0005162
CaseHPOFreeText: blood pressure of the four limbs was "92/44 mmHg at the right upper limb, 96/58 mmHg at the left upper limb, 101/60 mmHg at the right lower limb, and 103/54 mmHg at the left lower limb." Enlarged heart boundaries. Shifted apex.
CaseNotHPOs: HP:0000975
CaseNotHPOFreeText: decreased milk consumption
CasePreviousTesting: NR
Genotyping Method: genomic sequencing.
FunctionalAnalysis: NR
Variant: NM_001276345.2:c.548G>A
ClinVar:43649
CAID:CA004727
gnomAD: NR
AdditionalInfo:
The proband
Case#: Male, 17
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: All family members were asymptomatic, with normal TTE and ECG, with no evidence of VH.
ParentalTesting:
CasePresentingHPOs: HP:0001639, HP:0001279, HP:0001670, HP:0032092, HP:0031295
CaseHPOFreeText: diastolic type II dysfunction,
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: genetic analysis of the proband was performed through direct sequencing of the three sarcomere genes: MYH7, MYBPC3 and TNNT2
Genotyping Method: Sanger Sequencing
FunctionalAnalysis: NR
Variant: NR
ClinVar:NR
CAID: NR
gnomAD: NR
AdditionalInfo: underwent clinical and cardiovascular examination, including a 12-lead electrocardiogram (ECG), transthoracic echocardiography (TTE) and 24-hour Holter monitoring. TNNT2 sequenced, but not reported.
A 23-year-old female professional soccer player
Case1: Female, 23 years old, ethnicity not stated
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)
FamilyInfo: Mother, brother, and sister carry the same MYL2 mutation. Mother has phenotypic HCM without scar or high-risk features for sudden cardiac death. Sister and brother remain phenotypically negative with yearly imaging.
ParentalTesting: Maternal testing confirmed — mother carries the same MYL2 mutation and has phenotypic HCM. Paternal testing not reported.
CasePresentingHPOs: HP:0011675, HP:0001279, HP:0001962, HP:0004756
CaseHPOFreeText: During a sprinting drill, she developed a 42-second episode of polymorphic VT with spontaneous termination. The ambulatory rhythm monitoring showed a ~4% premature ventricular contraction (PVC) burden without sustained or nonsustained VT. CPET 2 demonstrated monomorphic nonsustained VT at peak exertion. Given exercise-induced polymorphic VT, she underwent placement of a subcutaneous implantable cardioverter-defibrillator (ICD) for secondary prevention. In the emergency department, high-sensitivity troponin rose from 105 to 303 ng/L. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis
CaseNotHPOs:HP:0100749, HP:0002094, HP:0031972, HP:0001714
CaseNotHPOFreeText: Normal LV size and function on echocardiography. Normal strain. Repeat cardiac MRI showed complete resolution of LGE. Normal biventricular size, thickness, and function without LGE or scar on third MRI. No sustained VT/VF after ICD placement. Normal complete blood count and basic metabolic panel. Coronary CT angiography unremarkable.
CasePreviousTesting: She underwent coronary computed tomography angiography to rule out ischemia and anomalous coronary origins, which was unremarkable. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis. Follow-up transthoracic echocardiography revealed normal LV size and function with normal strain, and repeat cardiac MRI showed complete resolution of LGE. She underwent maximal cardiopulmonary exercise testing (CPET), exercising for 13 minutes and 15 seconds, achieving 15 METs with a VO2 max of 40.4 mL/kg/min, which demonstrated frequent PVCs without nonsustained ventricular tachycardia (VT). Normal complete blood count and basic metabolic panel, aspartate aminotransferase, 38 U/L, alanine aminotransferase, 38 U/L, magnesium 2.2 mg/dL, thyroid-stimulating hormone, 1.96 μIU/mL, hemoglobin A1c, 5.8%.
Genotyping Method: Comprehensive genetic testing identified a pathogenic MYL2 variant.
FunctionalAnalysis: No functional analysis of the variant was performed
Variant: NM_000432.4:c.173G>A
ClinVar: 14067
CAID: CA009915
gnomAD: 12:111352091 C / T, chr12-110914287-C-T
AdditionalInfo: NR
The proband was a boy
Case1: Male, Infant, ethnicity not stated
DiseaseAssertion: congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy
FamilyInfo: The father was a healthy 20-yr old with no particular medical concerns, and there was no family history of neuromuscular or genetic disorders on either side. Both parents confirmed as heterozygous carriers of the MYL2 c.188del variant by Sanger sequencing
ParentalTesting: Both parents were confirmed as heterozygous carriers of MYL2 c.188del p.(Asn63Metfs7) by Sanger sequencing. Father confirmed as heterozygous carrier of NEB c.25435C>T p.(Gln8479)
CasePresentingHPOs: HP:0001290, HP:0001252, HP:0001640, HP:0001638, HP:0001639
CaseHPOFreeText: Newborn exam revealed normal first and second heart sound with gallop rhythm and palpable liver at the right costal margin, as well as generalized hypotonia and diminished reflexes. Echocardiogram was performed at 11 d of age and revealed patent foramen ovale with left to right shunt and right atrial enlargement. At age 5 mo, the proband was admitted to hospital in decompensated heart failure and intubated on inotropic support. Echocardiography revealed left ventricular dilatation, mild to moderate mitral valve regurgitation, and left atrial enlargement, with left ventricular function moderately to severely decreased with shortening fraction of 12% and ejection fraction of 23%. A vastus lateralis biopsy performed at 5 mo of age because of persistent muscle weakness and hypotonia revealed variability in fiber size with checkerboard pattern of 1:1 ratio of type 1 and type 2 fibers exhibiting hypotrophy of type 1 fiber size in comparison to the type 2 fibers. high lactate level (7.8 mmol/L)
CaseNotHPOs: NR
CaseNotHPOFreeText: Gomori trichrome–stained light micrographs and electron microscopy (EM) showed no evidence of ragged red fiber or nemaline rods, and oxidative stains revealed no evidence of cores, targetoid, or target fibers. Normal serum creatine kinase level. Normal birth weight, length, and head circumference. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Genetic testing for POLG and Noonan syndrome genes normal
CasePreviousTesting: Genetic testing was performed for DNA polymerase γ, catalytic subunit (POLG) and Noonan syndrome genes (PTPN11, SOS1, KRAS, RAF1, BRAF, MAP2K1, MAP2K2, and HRAS), all of which were normal. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Muscular dystrophy was considered unlikely given the histopathologic findings and normal serum creatine kinase level.
Genotyping Method: Next-generation sequencing was performed by the Laboratory for Molecular Medicine (LMM) of Partners Healthcare Personalized Medicine using the Agilent SureSelect Design process. The gene panel utilized an all exon approach for 43 genes of interest for neuromuscular and cardiac conditions by targeting coding exons with bait out to coding sequence (CDS) ±65 bases. The complete coding regions of all genes were sequenced to average depth of 316 reads
FunctionalAnalysis: No functional analysis of the variant was performed
Variant: NM_000432.3:c.188del
ClinVar: NR
CAID: UnregisteredVariant
gnomAD: NR
AdditionalInfo: This case also has a heterozygous pathogenic NEB variant c.25435C>T p.(Gln8479*) inherited from the father, classified as pathogenic but considered unlikely to be a significant contributor to disease as no second NEB allele was identified.
A 19-year-old woman was diagnosed with a reduced coagulation factor VIII activity of 30% after bleeding complications from wisdom tooth surgery
Case: Female, 19 y.o., ethnicity unknown.
DiseaseAssertion: VWD2N
FamilyInfo: Proband has one older symptomatic sister who shares an identical compound heterozygous genotype, presenting with a mild bleeding tendency, reduced FVIII activity (20-30%), and severely reduced FVIII binding (<2%). The family features one younger unaffected sister who tested negative for both variants, and an unaffected carrier mother. Both parents had normal factor VIII, and there was no male relative with reduced factor VIII or bleeding symptoms.
ParentalGenotype(s): Mother is heterozygous for the c.2561G>A (p.R854Q) variant, negative for the c.2402G>A (p.S801N) variant, and has normal baseline factor VIII levels, confirming the sisters' variants are in trans. Father unavailable/not tested.
CasePresentingHPOs: HP:0004846 (Prolonged bleeding after surgery), HP:0003645 (Prolonged partial thromboplastin time).
CaseHPOFreeText: Index patient experienced bleeding complications following wisdom tooth surgery. Factor VIII binding activity is reduced at 32%. Reduced coagulation factor VIII activity (30%). Prolonged activated partial thromboplastin time (aPTT) of 37 seconds.
CaseNOTHPOs: HP:0001873 (Thrombocytopenia), HP:0012147 (Reduced quantity of von Willebrand factor), HP:0030130 (Impaired von Willebrand factor collagen binding activity).
CaseNOTHPOFreeText: Normal vWF antigen (vWF:Ag) levels (101%), normal vWF activity (116%), normal vWF-collagen-binding activity (104%), normal vWF multimer distribution structures, normal hemoglobin level (128 g/L), and normal Prothrombin Time (PT/QUICK) of 83%.
CasePreviousTesting: Siblings did not carry any known mutations in the F8 gene or the LMAN1 and MCFD2 genes (which encode for endoplasmic reticulum carrier proteins of coagulation factors V and VIII).
GenotypingMethod: Direct sequence analysis of VWF exons 18-20.
PreviouslyPublished: NA.
Gene: VWF
HGNCID: HGNC:12726
Variant: Heterozygous c.2561G>A (p.R854Q) and heterozygous c.2402G>A (p.S801N).
HGVS: (1) NM_000552.5:c.2561G>A (p.Arg854Gln) (2) NM_000552.5:c.2402G>A (p.Ser801Asn)
ClinVarID: (1) 296 (2) NA
CAID: (1) NA (2) CA383522023
gnomAD: (1) MAF of 0.005974 in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4
(2) MAF of 0.00001098 in the South Asian population https://gnomad.broadinstitute.org/variant/12-6044331-C-T?dataset=gnomad_r4
three siblings
Case#: Eldest child, female, age at diagnosis and onset are unknown, age at treatment is 6, age at report is 11 DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0000280, HP:0008800, HP:0010501, HP:0006467, HP:0001659, HP:0001653, HP:0001634 (Coarse facial features, Limited hip movement, Limited shoulder movement, Limitation of knee mobility, Aortic regurgitation, Mitral regurgitation, Mitral valve prolapse) CaseHPOFreeText: Corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A
three siblings
Case#: Youngest child, Female, age at diagnosis and onset are unknown, age at treatment is 4 months, age at report is 5 years, 4 months DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: N/A CaseHPOFreeText: Mild corneal clouding, this study is to examine the efficacy of enzyme replacement therapy at different stages of teh disease, and it is assumed this patient is not yet old enough to have develped symptoms CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A
three siblings
Case#: Middle child, Male, age at diagnosis and onset are unknown, age at treatment is 2.5 years, age at report is 7.5 years DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0001634, HP:0001653 (mitral valve prolapse, mitral regurgitation) CaseHPOFreeText: Mild corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A
CasePT-104: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.4399C>G (p.Leu1467Val)
ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/
gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C
18
Case18: Male, 4 yr diagnosis, 5.2 yr report
HPOsFreeText: FVC z-score sitting -1.41 (82% pred), FVC z-score supine -1.96 (76% pred), 97% MRC Scale, 677 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
5
Case5: Male, 0.8 yr onset, 2.3 yr diagnosis, 9.5 yr report
HPOsFreeText: FVC z-score sitting -1.53 (82% pred), FVC z-score supine -1.71 (80% pred), 98% MRC Scale, 550 CK U/l, 15.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
29
Case29: Female, 6.5 yr onset, 11.6 yr diagnosis, 12.7 yr report
CasePresentingHPOs: HP:0001371 (Contractures)
HPOsFreeText: FVC z-score sitting -2.36 (73% pred), FVC z-score supine -2.89 (67% pred), 79% MRC Scale, 776 CK U/l, 8.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
20
Case20: Male, 14 yr diagnosis, 15.2 yr report
HPOsFreeText: FVC z-score sitting 3 (135% pred), FVC z-score supine 1.72 (120% pred), 1409 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
16
Case16: Male, 12 yr onset, 8 yr diagnosis, 14.6 yr report
HPOsFreeText: FVC z-score sitting -2.43 (71% pred), 82% MRC Scale, 1808 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
25
Case25: Male, 2.7 yr onset, 3.5 yr diagnosis, 5.9 yr report
HPOsFreeText: FVC z-score sitting 0.34 (104% pred), FVC z-score supine 0.04 (100% pred), 87% MRC Scale, 908 CK U/l, 2.8 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
21
Case21: Male, 16 yr diagnosis, 17.1 yr report
HPOsFreeText: FVC z-score sitting 1.29 (115% pred), FVC z-score supine -0.25 (97% pred), 1506 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
1
Case1: Male, 0.5 yr onset, 2.5 yr diagnosis, 10.04 yr report
CasePresentingHPOs: HP:0001371 (Contractures)
HPOsFreeText: Wheelchair used, FVC z-score sitting -0.25 (97% pred), FVC z-score supine -1.12 (87% pred), 65% MRC Scale, 530 CK U/l, 9.1 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No respiratory support
9
Case9: Male, 2 yr onset, 1 yr diagnosis, 6.6 yr report
HPOsFreeText: FVC z-score sitting -0.97 (89% pred), FVC z-score supine -1.4 (84% pred), 94% MRC Scale, 763 CK U/l, 11 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
11
Case9: Male, 5 yr onset, 10.8 yr diagnosis, 10.8 yr report
HPOsFreeText: FVC z-score sitting 0.2 (102% pred), FVC z-score supine -0.29 (97% pred), 97% MRC Scale, 588 CK U/l, 11.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
19
Case19: Male, 13.1 yr diagnosis, 13.1 yr report
HPOsFreeText: FVC z-score sitting -0.69 (92% pred), FVC z-score supine -1.77 (80% pred), 100% MRC Scale, 614 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
7
Case7: Male, 1 yr onset, 2 yr diagnosis, 13.7 yr report
CasePresentingHPOs: HP:0002650 (Scoliosis)
HPOsFreeText: Respiratory support at night, FVC z-score sitting -4.08 (54% pred), FVC z-score supine -5.4 (39% pred), 87% MRC Scale, 548 CK U/l, 17.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used
Patient 5
Case5: Female, Caucasian, United States, 2 months onset and diagnosis, 0.4 years report
CasePresentingHPOs: HP:0011968, HP:0011469, HP:0012378, HP:0004347, HP:0010453 (Feeding difficulties, Nasal regurgitation, Fatigue, Weakness of muscles of respiration, Pelvic bone asymmetry)
HPOsFreeText: Difficulty in lying supine while eating, sleeping and self-limited gasping episodes was observed, PT evaluation showed mild consistent asymmetry with increased lateral head tilt to the right, Tendency towards flexion/abduction/external rotation positioning of lower extremities was noted, Slight lateral thigh grooves reflected early IT band tightness with decreased posterior weight shift and propping on forearms in prone, AIMS score was at 10th percentile for chronological age and 25th to 50th percentile for corrected age, ALT 27 U/L (Normal 5–40 U/L), AST 36 U/L (Normal 15–41 U/L), ALP 352 U/L (Normal 24–170 U/L), Urinary Glc4 4.1 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)
CaseNotHPOs: HP:0002033, HP:0002015, HP:0004323, HP:0003808 (Poor suck, Poor swallowing, Abnormality of body weight, Abnormal muscle tone)
NotHPOsFreeText: CK levels, ECG, and ECHO have consistently been within normal limits, Had normal passive ranges of motion and appropriate weight bearing through lower extremities in supported standing
Patient 4
Case4: Female, Caucasian, United States, 1 month onset, 6 months diagnosis, 1.1 years report
CasePresentingHPOs: HP:0003236, HP:0012378, HP:0006589, HP:0003725 (Increased serum CK, Fatigue, Flaring of lower rib cage, Firm muscles)
HPOsFreeText: HyperCKemia present in the first month (505 IU/L; Normal 30–279 IU/L) but normalized spontaneously at 4 months (188 IU/L), PT assessment revealed subtle motor signs including preferred position of ring sitting with hips in flexion/abduction/external rotation and bilateral IT band tightness, Imbalanced trunk flexion, Decreased use of abdominals and excessive use of spinal extension, Asymmetry was noted in reaching objects in prone and weight shifting with lateral flexion and shortening on the left at the neck and trunk, AIMS score was at the 25th percentile and GMFM was 22.14%, Urinary Glc4 4.8 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)
CaseNotHPOs: HP:0003690 (Limb muscle weakness)
NotHPOsFreeText: She had no head lag when pulled to sit and the ability to transfer objects and bring them to midline
Patient 1
Case1: Male, Caucasian, United States, Birth onset
CasePresentingHPOs: HP:0008872, HP:0002100, HP:0001508, HP:0008947, HP:0001655, HP:0003236, HP:0200136, HP:0001290, HP:0002835, HP:0002194 (Feeding difficulties in infancy, Recurrent aspiration pneumonia, Poor weight gain, Infantile muscular hypotonia, Patent foramen ovale, Increased serum CK, Oropharyngeal dysphagia, Low muscle tone, Aspiration, Delayed gross motor development)
HPOsFreeText: HyperCKemia was present since the early neonatal period (378 IU/L, day 8 of life; N: 60–305 IU/L), ERT at a dose of 20 mg/kg every 2 weeks was initiated at age 1 month, CK levels were normalized on ERT by age 4 months (80 IU/L), Flexion/abduction/ external rotation positioning of lower extremities, iliotibial (IT) band tightness, lack of independent sitting, AIMS score between 10th and 25th percentile, GMFM at 23.16%, At age 23 months, he had achieved significant motor milestones; started sitting with support at 10 months and without support at 12 months, pulled to stand at 12 months, walked at 15 months and could feed himself with an immature pincer grasp. Swallow study was normal, ALT 26 U/L (Normal 5–40 U/L), AST 45 U/L (Normal 15–41 U/L), ALP 211 U/L (Normal 24–170 U/L), Urinary Glc4 3.7 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)
CaseNotHPOs: HP:0011675, HP:0002910 (ECG abnormality, Elevated hepatic transaminases)
NotHPOsFreetext:
CaseAddInfo: Older brother of Patient 2, Late-Onset Pompe Disease
Patient 2
Case2: Male, Caucasian, United States, Birth onset
CasePresentingHPOs: HP:0001290, HP:0200136, HP:0002033, HP:0003236, HP:0001655, HP:0002058, HP:0002194, HP:0002421, HP:0000467, HP:0002015 (Generalized hypotonia, Oral-pharyngeal dysphagia, Poor suck, Increased serum CK, Patent foramen ovale, Myopathic face, Delayed gross motor development, Poor head control, Neck muscle weakness, Dysphagia)
HPOsFreeText: hyperCKemia at 435 IU/L on day of life 4, Patent foramen ovale detected at birth by ECHO but resolved spontaneously, PT evaluation at age 2 months revealed flexion/abduction/external rotation positioning of lower extremities with tightness bilaterally in hip flexors, hamstrings, and IT bands, Had a tendency to remain on toes when held in supported standing with additional support required for weight bearing through lower extremities, Had difficulty lifting his head in prone, with asymmetric head lift to 45 degrees, and an inability to maintain head in midline when supine, AIMS score at age 2 months was between 10–25th percentile, ALT 41 U/L (Normal 5–40 U/L), AST 33 U/L (Normal 15–41 U/L), ALP 239 U/L (Normal 24–170 U/L), Urinary Glc4 4.5 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)
CaseNotHPOs: HP:0011016 (Abnormality of urine glucose concentration)
NotHPOsFreeText:
CaseAddInfo: Younger brother of Patient 1, Late-Onset Pompe Disease
Patient 7
Case7: Female, Caucasian, United States, 6 months diagnosis, 8 months report
CasePresentingHPOs: HP:0001643, HP:0006699, HP:0006682, HP:0003722, HP:0008969 (Patent ductus arteriosus, Premature atrial contractions, Premature ventricular contractions, Neck flexor weakness, Leg muscle stiffness)
HPOsFreeText: At 6 months head lag during pull to sit was noted, Had predominant overall flexion position of lower extremities with a tendency towards hip flexion/abduction/external rotation, with lateral thigh grooves suggestive of bilateral IT band tightness, AIMS score was between 10th and 25th percentile for chronological age and 50th percentile for her corrected age adjusted for prematurity while GMFM score was 16.55%, ALT 37 U/L (Normal 5–40 U/L), AST 53 U/L (Normal 15–41 U/L), ALP 174 U/L (Normal 24–170 U/L)
CaseNotHPOs: HP:0003236, HP:0001712, HP:0001290 (Increased serum CK, Left ventricular hypertrophy, Decreased muscle tone)
NotHPOsFreeText: Other evaluations including pulmonary, speech, and swallow were normal
Patient 6
Case6: Male, Caucasian, United States, 1 month onset, 6 months diagnosis, 8 months report
CasePresentingHPOs: HP:0003236, HP:0001655, HP:0003701, HP:0006589, HP:0003093, (Increased serum CK, Patent foramen ovale, Proximal muscle weakness, Flaring of lower rib cage, Limited hip extension,
HPOsFreeText: HyperCKemia was noticed in the first month (438 U/L; Normal 60–305) but normalized spontaneously by age 6 months, flexion/abduction/external rotation positioning of lower extremities and with bilateral IT band tightness was revealed at the same time, also had decreased active use of abdominal oblique muscles with a lack of active trunk rotation, Decreased active use of lower abdominal muscles with inability to achieve a posterior pelvic tilt in supine, AIMS score was at 1st percentile for age and GMFM was at 12.3%, ALT 30 U/L (Normal 5–40 U/L), AST 90 U/L (Normal 15–41 U/L), ALP 249 U/L (Normal 24–170 U/L), Urinary Glc4 2.6 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)
CaseNotHPOs: HP:0001712, HP:0001290 (Left ventricular hypertrophy, Decreased muscle tone)
NotHPOsFreeText: Other evaluations including cardiac, pulmonary, speech, and swallow were normal
one confirmed LOPD patient
Case1: Female, 55 years report, 25 years onset, Brazil, African
CasePresentingHPOs: HP:0003325, HP:0003236, HP:0003148, HP:0100284, HP:0011807, HP:0003326, HP:0008994, HP:0002527, HP:0003551, HP:0002015, HP:0000822, HP:0000819, HP:0003119, HP:0003707, HP:0003391, HP:0003327, HP:0001315, HP:0002515, HP:0010546 (Limb-girlde muscle weakness, Increased serum CK, Elevated serum acid phosphatase, EMG: myotonic discharges, Type 1 muscle fiber atrophy, Myalgia, Proximal muscle weakness in lower limbs, Falls, Difficulty climbing stairs, Dysphagia, Hypertension, Diabetes mellitus, Dyslipidemia, Calf muscle pseudohypertrophy, Gowers sign, Axial muscle weakness, Reduced deep tendon reflexes, Waddling gait, Muscle fibrillation)
HPOsFreeText: Serum CK 1467 U/L (normal: ≤ 200U/L), NaG/AaGIA ratio 40.4, %INH 87.2, GAA activity 4.2% from dried blood spot, Falls occurring mainly when walking for long distances, Normal Mini-Mental State Examination score (27/30), Mild symmetrical weakness in proximal muscles in the lower limbs (Medical Research Council grade 4), Needle electromyography revealed motor unit potentials with low amplitude and short duration in the iliopsoas muscle associated with fibrillation and short myotonic discharge potentials in lumbar paraspinal muscles
CaseNotHPOs: HP:0001270 (Motor delay)
NotHPOsFreeText: Muscle biopsy with the absence of vacuolar myopathy
CaseAddInfo: Late-Onset Pompe Disease, One sister diagnosed with LOPD based on low GAA activity and shared genetic variants but no other known relatives with the condition
10
Case10: Female, 15 years report, Italy
HPOsFreeText: Height is 1.60 m, Weight is 59 kg, BMI is 23.0 kg/cm2, 8 years on ERT, Forced Vital Capacity at 106%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
3
Case3: Male, 19 years report, Italy
CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)
HPOsFreeText: Height is 1.78 m, Weight is 60 kg, BMI is 18.9 kg/cm2, 7 years on ERT, Forced Vital Capacity at 107%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
11
Case11: Female, 16 years report, Italy
HPOsFreeText: Height is 1.62 m, Weight is 57 kg, BMI is 21.7 kg/cm2, 7 years on ERT, Forced Vital Capacity at 102%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
4
Case4: Male, 17 years report, Italy
HPOsFreeText: Height is 1.88 m, Weight is 66 kg, BMI is 18.7 kg/cm2, 7 years on ERT, Forced Vital Capacity at 91%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
6
Case6: Male, 21 years report, Italy
HPOsFreeText: Height is 1.74 m, Weight is 71 kg, BMI is 23.5 kg/cm2, 7 years on ERT, Forced Vital Capacity at 99%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
1
Case1: Female, 46 years report, Italy
CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)
HPOsFreeText: Height is 1.64 m, Weight is 50 kg, BMI is 18.6 kg/cm2, 2 years on ERT, Forced Vital Capacity at 108%
CaseNotHPOs: HP:0002098 (Respiratory distress)
NotHPOsFreeText: Nocturnal non-invasive ventilation
CaseAddInfo: Late Onset Pompe Disease
II
CaseII: Adult onset, 71 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003326, HP:0003236, HP:0003198 (Proximal muscle weakness, Myalgia, Increased serum CK, Myopathy)
HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from dried blood spot: 0%, 6-Minute Walking Test: 40 min, Forced Vital Capacity Seated: 850 (22%)
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
IX
CaseIX: Early adult onset
CasePresentingHPOs: HP:0003701, HP:0003388, HP:0002795, HP:0001627 (Proximal muscle weakness, Easy fatiguability, Abnormal respiration, Abnormal heart morphology)
HPOsFreeText: Wheelchair-bound
CaseAddInfo: Late-Onset Pompe Disease
1
CaseV,1: Adolescent onset, 42 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326 (Proximal muscle weakness, Increased serum CK, Easy fatigability, Myalgia)
HPOsFreeText: Plasma CK 5-10× Normal, Vacuoles in histology, 6-Minute Walking Test: 135 min, Forced Vital Capacity Seated: 950 (20%), GAA activity from dried blood spot: 0.20%
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
1
CaseIV,1: Early adult onset, 40 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002795, HP:0003546 (Proximal muscle weakness, Increased serum CK, Abnormal respiration, Exercise intolerance)
HPOsFreeText: Plasma CK 2.5–5× Normal, Vacuoles in histology
CaseAddInfo: Late-Onset Pompe Disease
3
CaseV,3: Child onset, 45 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236 (Proximal muscle weakness, Increased serum CK)
HPOsFreeText: Plasma CK 2.5-5× Normal, GAA activity from dried blood spot: 0.08%, 6-Minute Walking Test: 566 min
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
III
CaseIII: Adult onset, 63 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198, HP:0002460, HP:0002015 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy, Distal muscle weakness, Dysphagia)
HPOsFreeText: Plasma CK 2.5–5× Normal, GAA activity from muscle: 11.7%
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
4
CaseIV,4: Early adult onset, 45 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003546 (Proximal muscle weakness, Increased serum CK, Exercise intolerance)
HPOsFreeText: Plasma CK 2.5–5× Normal, Vacuoles in histology
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
I
CaseI: Early adult onset, 49 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy)
HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from lymphocytes: 14.2%
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
3
CaseIV,3: Early adult onset, 50 years diagnosis
CasePresentingHPOs: HP:0003236, HP:0003546 (Increased serum CK, Exercise intolerance)
HPOsFreeText: Plasma CK 2.5–5× Normal
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
2
CaseV,2: Adult onset, 33 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388 (Proximal muscle weakness, Increased serum CK, Easy fatigability)
HPOsFreeText: Plasma CK 5-10× Normal, 6-Minute Walking Test: 566 min, Forced Vital Capacity Seated: 3000 (90%), GAA activity from dried blood spot: 0.20%
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
2
CaseIV,2: Early adult onset, 47 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002795, HP:0003546 (Proximal muscle weakness, Increased serum CK, Abnormal respiration, Exercise intolerance)
HPOsFreeText: Plasma CK 2.5–5× Normal
CaseAddInfo: Late-Onset Pompe Disease
9
Case9: Male, 40 years onset, 45 years diagnosis, 74 years report, France
CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)
HPOsFreeText: Lost ambulation at 50 years, Started invasive ventilation at 67 years, Started ERT given every other week at a dose of 20 mg/kg at 70 years for 43 months, Peak Anti-rhGAA antibodies at 1:409,600, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 29 to 26, 6MWT stayed constant at 0 meters
CaseNotHPOs: HP:0030148 (Heart murmur)
NotHPOsFreeText: No adverse reaction to ERT was recorded
CaseAddInfo: Late Onset Pompe Disease
12
Case12: Male, 35 years onset, 50 years diagnosis, 61 years report, France
CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)
HPOsFreeText: Lost ambulation at 48 years, Started invasive ventilation at 35 years, Started ERT given every other week at a dose of 20 mg/kg at 56 years for 49 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0 (L / % expected), MIP at 22 (cm H2O), MEP at 28 (cm H2O), Time off ventilation stayed constant at 0 min, 6MWT stayed constant at 0 meters
CaseNotHPOs: HP:0030148 (Heart murmur)
NotHPOsFreeText: No adverse reaction to ERT was recorded
CaseAddInfo: Late Onset Pompe Disease
3
Case3: Male, 28 years onset, 30 years diagnosis, 69 years report, France
CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficency)
HPOsFreeText: Lost ambulation at 58 years, Started invasive ventilation at 28 years, Started ERT given every other week at a dose of 20 mg/kg at 68 years for 11 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0.45/13 (L / % expected), MIP at 17 (cm H2O), MEP at 29 (cm H2O), Time off ventilation stayed constant at 0, Total Motor Function Measure from 31 to 27
CaseNotHPOs: HP:0030148 (Heart murmur)
NotHPOsFreeText: No adverse reaction to ERT was recorded
CaseAddInfo: Late Onset Pompe Disease, Patient died before publication
62-year-old man
Case1: Male, 62 years report
CasePresentingHPOs: HP:0002091, HP:0002878, HP:0003701, HP:0040047, HP:0002098, HP:0100786, HP:0006510, HP:0005978, HP:0000822, HP:0003124, HP:0001677, HP:0003236, HP:0004324, HP:0002329, HP:0030207, HP:0002098, HP:0040047, HP:0100750, HP:0002097, HP:0007269, HP:0040046 (Restrictive lung disease, Respiratory failure, Proximal muscle weakness, Abnormality of the right hemidiaphragm, Shortness of breath, Hypersomnia, Chronic obstructive pulmonary disease, Diabetes mellitus Type II, Hypertension, Hypercholesterolemia, Coronary artery disease, Elevated serum creatine kinase, Increased body weight, Drowsiness, Paradoxical respiration, Respiratory distress, Abnormality of the right hemidiaphragm, Atelectasis, Emphysema, Spinal muscular atrophy, Abnormality of the left hemidiaphragm)
HPOsFreeText: Hypercapnic respiratory failure, Chronic phrenic neuropathy bilaterally, Long history of apparently idiopathic right hemidiaphragm paralysis, Underwent muscle biopsy and electromyography, both of which showed nonspecific myopathic features associated with mild denervation, On presentation, the patient's vital signs were a temperature of 36.5 °C (97.7 °F); heart rate, 94 beats/minute; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/minute; oxygen saturation, 90% when receiving 2 L of supplemental oxygen per minute; and body mass index, 29.9 kg/m2, Decreased air entry bilaterally, Laboratory values were: Hemoglobin, 120 g/L; platelets, 279 × 109/L; white blood cells, 7.7 × 109/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; bicarbonate, 40 mmol/L; serum urea nitrogen, 3.6 mmol/L; creatinine, 70.7 μmol/L; and calcium, 2.48 mmol/L, Fatty atrophy of rotator cuff musculature, Tests for resting room-air arterial blood gases showed a pH of 7.29; PCO2, 89.4 mm Hg; PO2, 67.6 mm Hg; and serum bicarbonate, 43 mmol/L, Right diaphragm paralysis, Electromyography showed complete absence of phrenic compound muscle action potentials bilaterally. No activation of motor unit potentials was seen within the diaphragm, either with respiration or with volitional effort. Ultrasonography showed that the left hemidiaphragm was hyperechoic, 0.14 cm thick at functional residual capacity (FRC), with a thickening ratio of 1.1 (the thickening ratio is thickness at total lung capacity/thickness at FRC). The right hemidiaphragm was hyperechoic, 0.15 cm thick at FRC, with thickening ratio of 0.9. (Normal thickness is >0.15 cm, normal thickening ratio is >1.2.) The aldolase concentration was slightly increased at 9 U/L (reference level, <7.7 U/L). To complete the evaluation for rarer causes of diaphragmatic dysfunction, neurology services requested testing for inherited neuropathies. Three weeks later, the patient's serum GAA level was 1.0 nmol/mL/hour (reference level, >7.4 nmol/mL/hour)
CaseNotHPOs: HP:0003549 (Abnormality of connective tissue)
NotHPOsFreeText: The following tests were within reference range: creatine kinase, thyroid function tests, erythrocyte sedimentation rate, serum and protein electrophoresis, antinuclear antibody profile, and anti-Jo antibodies
CaseAddInfo: Ex-Smoker with 40–80 pack-years of smoking, Medications at presentation to facility included aspirin, clopidogrel, simvastatin, diltiazem, sitagliptin, metformin, budesonide and formoterol inhaler, tiotropium bromide inhaler, and albuterol inhaler
1
Case1: Male, 21 years onset, 27 years diagnosis, 36 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
4a
Case4a: Male, 46 years onset, 46 years diagnosis, 56 years report
CasePresentingHPOs: HP:0003236, HP:0002747 (Increased serum CK, Respiratory muscle weakness)
CaseAddInfo: Late-Onset Pompe Disease, Sibling of Patient 4
boy
CaseA: Male, 10 months onset, 18 months diagnosis
CaseAPresentingHPOs: HP:0001270, HP:0003324 (Motor delay, Generalized weakness)
HPOsFreeText: CRIM positive
CaseNotHPOs: HP:0100543 (Cognitive impairment)
CaseAddInfo: Infantile-Onset Pompe Disease
4
Case4: Female, 25 years onset, 43 years diagnosis, 58 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, Sibling of Patient 4a
8
Case8: Female, 18 years onset, 18.5 years diagnosis, 29 years report
CasePresentingHPOs: HP:0003325, HP:0003236 (Limb-girdle muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
14
Case14: Male, 28 years onset, 36 years diagnosis, 37 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Scapula alata)
CaseAddInfo: Late-Onset Pompe Disease
10
Case10: Female, 47 years onset, 50 years diagnosis, 64 years report
CasePresentingHPOs: HP:0003325, HP:0003236 (Limb-girdle muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
#12
Case12: Male, 15 years onset, 40 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
#15
Case15: Female, 13 years onset, 43 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
#20
Case20: Female, 3 years onset, 4 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
3
Case3: Male, 1 year report
CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)
HPOsFreeText: Nonspecific hyperCKemia, 847 CK (U/L), 0 GAA activity (µmol/L/h)
CaseNotHPOs: HP:0001627, HP:0002093 (Abnormality of the heart, Respiratory insufficiency)
2
Case2: Male, 2 years report
CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)
HPOsFreeText: Nonspecific hyperCKemia, 1710 CK (U/L), 0.1 GAA activity (µmol/L/h)
CaseNotHPOs: HP:0003457, HP:0001627, HP:0002093 (EMG abnormality, Abnormality of the heart, Respiratory insufficiency)
1
Case1: Female, 12 years report, 3 years onset, 12 years diagnosis
CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002650 (Limb-girdle muscle weakness, Respiratory insufficiency, Scoliosis)
HPOsFreeText: 730 CK (U/L), Normal Heart, 0 GAA activity (µmol/L/h), Showed respiratory involvement and required nocturnal non-invasive ventilation, An ambulant patient with 284 m six minute walk distance at the time of diagnosis
CaseNotHPOs: HP:0003457, HP:0001627 (EMG abnormality, Abnormality of the heart)
NotHPOsFreeText: Muscle weakness confined to limb-girdle muscles
P2
PatientF2P2: Female, 39 years diagnosis, Caucasian
CasePresentingHPOs: HP:0003323, HP:0003198, (Progressive muscle weakness, Myopathy)
HPOsFreeText: Had deficient muscle acid GAA activity (1.0 mmol/min/g, control >4.0 mmol/min/g)
CaseAddInfo: Mother of F2P1, the proband, who died at 8 months secondary to the disease.
4
Case4: 0.5 years diagnosis, Germany
CasePresentingHPOs: HP:0031185, HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Increased NT-proBNP level, Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)
HPOsFreeText: 3924 BNP (pg/ml), 7.68 IVS (d) z score, 6.42 IVS (s) z score, Heart Failure at NYHA Class 3
NotHPOsFreeText: No left-ventricular outflow tract obstruction
CaseAddInfo: Infantile-Onset Pompe Disease
5 mg/kg (N = 3)
Case3HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 3.1 pmol/punch/hr, GAA activity at 31% lower limit of normal
CaseAddInfo: Late Onset Pompe Disease
1117
Case1117: Male, 35 years onset, Welsh/English, Caucasian
CasePresentingHPOs: HP:0003560, HP:0005110 (Muscular dystrophy, Atrial fibrillation)
HPOsFreeText: 1,000 –2000's CK level, Immunohistochemistry: dystrophin, sarcoglycans, merosin
CaseNotHPOs: HP:0009051, HP:0002540 (Increased muscle glycogen content, Non-ambulatory)
Patient Number 3
Case3: Male, 35 years report, 5 years onset, Algeria, African
CasePresentingHPOs: HP:0003323, HP:0003749, HP:0002355, HP:0007340, HP:0008956, HP:0003484, HP:0003236, HP:0003198 (Progressive muscle weakness, Pelvic girdle muscle weakness, Difficulty walking, Lower limb muscle weakness, Proximal lower limb amyotrophy, Upper limb muscle weakness, Increased serum CK, Myopathy)
HPOsFreeText: At grade 3 of Vignos and Walton scales, CK rate was 5 times the normal value and AST and ALT were normal, EMG was compatible with a myopathic disorder, GAA activity measured in leukocytes was significantly decreased
CaseNotHPOs: HP:0003115, HP:0003116, HP:0001270, HP:0001290, HP:0002240, HP:0001640, HP:0005952, HP:0002540 (Abnormal ECG, Abnormal echocardiography, Motor delay, Generalized hypotonia, Hepatomegaly, Cardiomegaly, Decreased pulmonary function, Non-ambulatory)
15
Patient15: Male, 21 years report, 2 years onset
CasePresentingHPOs: N/A
HPOsFreeText: GAA activity 4.7% from a dried blood spot
CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
The affected patient
Case1: Male, French-Canadian, 18 years onset, 54 years diagnosis and report
CasePresentingHPOs: HP:0008994, HP:0000822, HP:0003119, HP:0004398, HP:0007185, HP:0009109, HP:0002094, HP:0012764, HP:0002098 (Proximal muscle weakness in lower limbs, High blood pressure, dyslipidemia, Peptic ulcer, Loss of consciousness, Denervation of the diaphragm, Dyspnea, Orthopnea, Shortness of breath)
HPOsFreeText: Dependent on continuous positive airway pressure or bilevel positive airway pressure when he is lying flat or sleeping because of previous intubation and tracheostomy, GAA activity measured from dried blood spot was 0.87 pmol/h/punch (Normal 4.96 - 27.3)
CaseAddInfo: Late Onset Pompe Disease, The patient’s mother had six miscarriages and died at age 75 of lung cancer and his father died of cardiac problems in his early sixties, It appears that no other family members, including his parents and two siblings, were affected, patient had a previous appendectomy, He has no allergies, stopped smoking in 2002, and denied any alcohol or drug use
10
Case9: 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
(Prolonged clotting time)
CaseHPOFreeText: Bleeding time greater than 20 minutes and hematocrit of 38.1%
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: 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.1392A>G (p.Pro464Pro)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA500273575
gnomAD: https://gnomad.broadinstitute.org/variant/17-42458248-T-C
RL
Case4: Patient RL
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.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case20: GT23, Male, 19, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000225, HP:0000421
(Easy bruising, gingival bleeding, epistaxis)
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.1031A>C (p.Tyr344Ser)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025814
gnomAD: N/A