a 19‐year‐old
Case1:19 Year-old male
DiseaseAssertion:HCM
FamilyInfo:None documented
ParentalTesting:
CasePresentingHPOs:HP:0001639
CaseHPOFreeText:Hypertrophic Cardiomyopathy
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:
Genotyping Method:Next Generation Sequencing
FunctionalAnalysis:
Variant:c.442G>A, (p.Gly148Arg)
ClinVar:42752
CAID: CA015105
gnomAD:NR
AdditionalInfo:NR
healthy 46 years old active, athletic, healthy individual
Case1:Male, 46 years old
DiseaseAssertion:NR
FamilyInfo: 3 generations of asymptomatic carriers
ParentalTesting:NR
CasePresentingHPOs:NR
CaseHPOFreeText:
CaseNotHPOs:HP:0001712
CaseNotHPOFreeText:Left Ventricular hypertrophy
CasePreviousTesting:NR
Genotyping Method: NR
FunctionalAnalysis:
Variant: c.170C>A VUS
ClinVar:43121
CAID:CA013575
gnomAD: NR
AdditionalInfo:
proband (1-II-3)
Case1:Female diagnosed at 28
DiseaseAssertion:HCM, ASH, LVEF
FamilyInfo:Sister with HCM, ASH, and mid-LV cavity obstruction
ParentalTesting:NR
CasePresentingHPOs:HP:0001639, HP:0001670, HP:0034314, HP:0001279
CaseHPOFreeText:Hypertrophic cardiomyopathy, Asymmetric Septal Hypertrophy, Abnormal Left Ventricular Ejection Fraction, Syncope
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:NR
Genotyping Method:Not detailed
FunctionalAnalysis:MYL3 A57G
Variant:c.170C>G (p.Ala57Gly)
ClinVar:31780
CAID:CA013589
gnomAD:NR
AdditionalInfo:NR
7
Patient7: Male
CasePresentingHPOs: HP:0002194
HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive
CaseNotHPOs: HP:0004887
NotHPOsFreeText: no reversal of HCM
CaseAddInfo: Symptom onset and diagnosis at 3mo, ERT at 4mo, ERT lasted for 24mo, 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
11
Patient11: Female
CasePresentingHPOs: HP:0004887, HP:0002100, HP:0006597, HP:0200136, HP:0011471
HPOsFreeText: ERT dosage = 40mg/kg/w, HCM reversal, CRIM positive, able to run, diaphragmatic paralysis required plication at 3yo
CaseNotHPOs: HP:0009046
NotHPOsFreeText:
CaseAddInfo: Symptom onset at 2mo, diagnosis at 4mo, ERT at 5mo, ERT lasted for 67mo, ventilation required at 62mo, currently 6yo
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
15
Patient15: Male
CasePresentingHPOs: HP:0002194, HP:0004887, HP:0001522, CRIM positive
HPOsFreeText: ERT Dosage = 20mg/kg/2w, HCM reversal
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: Symptom onset at 4mo, diagnosis and ERT at 9mo, ERT lasted for 12mo, ventilation required at 10mo, died at 21mo
CasePMIDs: 11738358
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1082C>T (p.Pro361Leu)
ClinVar: 403712, https://www.ncbi.nlm.nih.gov/clinvar/variation/403712/
gnomAD: 8.469e-06, http://exac.broadinstitute.org/variant/17-78082294-C-T
14
Patient14: Female
CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522
HPOsFreeText: ERT dosage = 20mg/kg/2w, was able to crawl but this ability was eventually lost, CRIM positive
CaseNotHPOs:
NotHPOsFreeText: no HCM reversal
CaseAddInfo: Symptom onset at 4mo, diagnosis at 8mo, ERT at 9mo, ERT lasted for 1mo, ventilation required at 8mo, died at 10mo
CasePMIDs: 11738358
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: 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
CaseOPTPD-5: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.27 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.1222A>G (p.Met408Val)
ClinVar: 371235 https://www.ncbi.nlm.nih.gov/clinvar/variation/371235/
gnomAD: European (Non-Finnish) 1.790e-5, Overall 8.058e-6 http://gnomad.broadinstitute.org/variant/17-78082523-A-G
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
CaseLP2-12: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.43 umol/hr/L, Serum CK at 29 U/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: 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
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
Variant3: NM_000152.4:c.2482-5T>C
ClinVar: 558320 https://www.ncbi.nlm.nih.gov/clinvar/variation/558320/
gnomAD: Not in gnomAD
CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis one one allele and Variants 2 and 3 are in cis on the other
CaseOPOPD-52: 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.1843G>A (p.Gly615Arg)
ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/
gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has the same genotype
CaseOPOPD-45: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.46 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.1411_1414delGAGA (p.Glu471Profs)
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
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, 1 other has the same genotype
CaseOPOPD-4: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.16 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.460_465del (p.Arg154_Thr155del)
ClinVar: 551306 https://www.ncbi.nlm.nih.gov/clinvar/variation/551306/
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)
ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/
gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A
CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation
CaseOPTPD-79: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.75 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.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: 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, 5 other patients have the same genotype
CaseOPOPD-53: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.23 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.1843G>A (p.Gly615Arg)
ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/
gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has the same genotype
CaseOPOPD-6: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.75 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.569G>A (p.Arg190His)
ClinVar: 188809 https://www.ncbi.nlm.nih.gov/clinvar/variation/188809/
gnomAD: African 6.166e-5, Overall 1.602e-5 http://gnomad.broadinstitute.org/variant/17-78079570-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 and One Pseudodeficency Mutation, 2 others have the same genotype
CaseOPOPD-44: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.51 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.1222A>G (p.Met408Val)
ClinVar: 371235 https://www.ncbi.nlm.nih.gov/clinvar/variation/371235/
gnomAD: European (Non-Finnish) 1.790e-5, Overall 8.058e-6 http://gnomad.broadinstitute.org/variant/17-78082523-A-G
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
CaseIP2-3: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.04 umol/hr/L, Serum CK at 809 U/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.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 2 and 3 are in trans
CaseOPOPD-39: Male, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 1.56 umol/hr/L
GenotypingMethod: GAA Gene Sequencing and PCR Amplification
Variant1: NM_000152.4:c.841C>T (p.Arg281Trp)
ClinVar: 283894 https://www.ncbi.nlm.nih.gov/clinvar/variation/283894/
gnomAD: European (Non-Finnish) 4.051e-4, Overall 2.051e-4 http://gnomad.broadinstitute.org/variant/17-78081504-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
CaseOPOPD-65: Female, Taiwan, Birth diagnosis
HPOsFreeText: GAA (MS/MS) enzyme activity at 0.77 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.2185delC (p.Leu729Trpfs)
ClinVar: 370552 https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/
gnomAD: Not in gnomAD
CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has this genotype
c.1441T > C(p.Trp481Arg)
Case59
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.1441T>C (p.Trp481Arg)
ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/
gnomAD: African 8.031e-5, Overall 2.126e-5 http://gnomad.broadinstitute.org/variant/17-78084529-T-C
Variant2: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
CaseAddInfo: Adult Late Onset Pompe Disease
c.925G > A(p.Gly309Arg)
Case90
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.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
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, 1 other patient has the same genotype
c.2238G > A(p.Trp746*)
Case69
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.2238G>A (p.Trp746*)
ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/
gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-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, 1 other patient has the same genotype
c.2238G > A(p.Trp746*)
Case35
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.2238G>A (p.Trp746*)
ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/
gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A
Variant2: NM_000152.4:c.1843G>A (p.Gly615Arg)
ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/
gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A
CaseAddInfo: Infantile Onset Pompe Disease
c.2481+102_2646+31del (p.Gly828_Asn882del)
Case38
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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)
ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/
gnomAD: Not in gnomAD
Variant2: NM_000152.4:c.1912G>T (p.Gly638Trp)
CAID: 280954 https://www.ncbi.nlm.nih.gov/clinvar/variation/280954/
gnomAD: African 6.752e-5, Overall 1.239e-5 http://gnomad.broadinstitute.org/variant/17-78086698-G-T
CaseAddInfo: Infantile Onset Pompe Disease
c.2560C > T(p.Arg854*)
Case24
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.2459_2461delCTG (p.Ala820del)
ClinVar: 456404 https://www.ncbi.nlm.nih.gov/clinvar/variation/456404/
gnomAD: European (Non-Finnish) 6.492e-5, Overall 3.190e-5 http://gnomad.broadinstitute.org/variant/17-78091524-GGCT-G
CaseAddInfo: Infantile Onset Pompe Disease
c.2237G > A(p.Trp746*)
Case11
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.2237G>A (p.Trp746*)
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
Variant2: NM_000152.4:c.437delT (p.Met146Argfs*7)
ClinVar: 554096 https://www.ncbi.nlm.nih.gov/clinvar/variation/554096/
gnomAD: Not in gnomAD
CaseAddInfo: Infantile Onset Pompe Disease
c.1548G > A(p.Trp516*)
Case62
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.1548G>A (p.Trp516*)
ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/
gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-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, 1 person more with the same genotype
c.1826dupA(p.Tyr609*)
Case9
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.1826dupA (p.Tyr609*)
ClinVar: 189144 https://www.ncbi.nlm.nih.gov/clinvar/variation/189144/
gnomAD: European (Non-Finnish) 1.816e-5, Overall 8.159e-6 http://gnomad.broadinstitute.org/variant/17-78086447-T-TA
Variant2: NM_000152.4:c.2238G>A (p.Trp746*)
ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/
gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A
CaseAddInfo: Infantile Onset Pompe Disease
c.1438-1G > C
Case31
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.1438-1G>C
ClinVar: 189184 https://www.ncbi.nlm.nih.gov/clinvar/variation/189184/
gnomAD: African 1.150e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78084525-G-C
Variant2: NM_000152.4:c.1655T>C (p.Leu552Pro)
ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/
gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C
CaseAddInfo: Infantile Onset Pompe Disease
c.2560C > T(p.Arg854*)
Case13
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.1292_1295dupTGCA (p.Gln433Alafs*74)
ClinVar: 552165 https://www.ncbi.nlm.nih.gov/clinvar/variation/552165/
gnomAD: African 6.992e-5, Overall 4.293e-6 http://gnomad.broadinstitute.org/variant/17-78082592-C-CTGCA
CaseAddInfo: Infantile Onset Pompe Disease
c.1143delC(p.Ala382Leufs*10)
Case92
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)
ClinVar: 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, 1 other patient has the same genotype
c.2242dupG (p.Glu748Glyfs*48)
Case71
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.2242dupG (p.Glu748Glyfs*48)
ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/
gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 http://gnomad.broadinstitute.org/variant/17-78090813-T-TG
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.655G > A(p.Gly219Arg)
Case48
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.655G>A (p.Gly219Arg) (p.Glu176Argfs*45)
ClinVar: 189065 https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: African 4.024e-5, Overall 1.809e-5 http://gnomad.broadinstitute.org/variant/17-78079656-G-A
CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant
30
Patient30: Female, 1 year onset
CasePresentingHPOs: HP:0001324, HP:0001263 (Muscle weakness, Developmental delay)
HPOsFreeText: GAA activity 3% from leukocyte
CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
19
Patient19: Male, 21 years report, 14 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 9.3% from leukocyte, Respiratory Assistance needed
CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: Wheelchair not needed
CaseAddInfo: LOPD
14
Patient14: Male, 59 years report, 40 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 6.9% from dried blood spot, Respiratory Assistance needed
CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: Wheelchair not needed
CaseAddInfo: LOPD
20
Patient20: Male, 22 years report, 12 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 11.6% from leukocyte, Respiratory Assistance needed
CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)
NotHPOsFreeText: Wheelchair not needed
CaseAddInfo: LOPD
33
Patient33: Female, 24 years report, 3 year onset
CasePresentingHPOs: HP:0001324 (Muscle weakness)
HPOsFreeText: GAA activity 9.6% from leukocyte
CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
12
Patient12: Male, 19 years report, 13 years onset
CasePresentingHPOs: HP:0001324 (Muscle weakness)
HPOsFreeText: GAA activity 9.9% from leukocyte
CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
29
Patient29: Female, 30 years onset
CasePresentingHPOs: HP:0001324, HP:0001288 (Muscle weakness, Gait disturbance)
HPOsFreeText: GAA activity 4% from leukocyte
CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: LOPD
18
Patient18: Female, 48 years report, 42 years onset
CasePresentingHPOs: N/A
HPOsFreeText: GAA activity 8.1% from leukocyte
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
23
Patient23: Male, 68 years report, 2.5 year onset
CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)
HPOsFreeText: GAA activity 9.8% from leukocyte, Respiratory Assistance needed
CaseNotHPOs: HP:0002240 (Hepatomegaly)
NotHPOsFreeText: N/A
CaseAddInfo: LOPD
4
Patient4: Male, 5 years report, 1 year onset
CasePresentingHPOs: HP:0001640 (Cardiomegaly)
HPOsFreeText: GAA activity 3.5% from leukocyte
CaseNotHPOs: HP:0002098, HP:0001324, HP:0002240 (Respiratory distress, Muscle weakness, Hepatomegaly)
NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed
CaseAddInfo: IOPD
1
Case#: 1, age 36, age 30 (report)
DiseaseAssertion: Pompe Disease
FamilyInfo: Family 1, no further information
CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)
CaseHPOFreeText: myopathy with vacuoles, biopsy with vacuolar myopathy with PAS +
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: single gene sequencing/analysis, 48.47 NaG/AaGIA, 89.61% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range
Variants:
Variant 1:NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)
ClinVar: 550327
Variant 2: Not reported
ParentalGenotypes: N/A
PreviouslyPublished: N/A
2/b
Case#: 2/b, age 11, age 5 (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, 105.01 NaG/AaGIA, 90.98% 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
Supplement Table 1)
Patient1: 7yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA dosage = 20QW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 17days old at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.4(GAA):c.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
Supplement Table 1)
Patient12: 8yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA dosage = 20 EOW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 26days old at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)
ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/
gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C
Supplement Table 1)
Patient6: 7yo
CasePresentingHPOs: HP:0001638
HPOsFreeText: rhGAA = 20 EOW, independent walker
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 3mo at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)
ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/
gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A
Variant2: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)
ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/
gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C
P2
Patient2: Female, 37yo
CasePresentingHPOs: HP:0003077, HP:0001513
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 10yr disease duration, ERT lasted for 33mo
CasePMIDs: PMID: 25614309
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)
ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/
gnomAD: n/a
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
P15
Patient15: Female, 56yo
CasePresentingHPOs: HP:0003077, HP:0000822
HPOsFreeText: LOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 19yr disease duration, ERT lasted 48mo
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
7
Case7: Female, 3 years onset, 3 years diagnosis, 27 years report, France
CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)
HPOsFreeText: Lost ambulation at 11 years, Started invasive ventilation at 11 years, Started ERT given every other week at a dose of 20 mg/kg at 18 years for 114 months, Peak Anti-rhGAA antibodies at 1:102,400, FVC at 0.22/6 (L / % expected), MIP at 10 (cm H2O), MEP at 10 (cm H2O), Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 23 to 19, 6MWT stayed constant at 0 meters
CaseNotHPOs: HP:0030148 (Heart murmur)
NotHPOsFreeText: No adverse reaction to ERT was recorded
CaseAddInfo: Late Onset Pompe Disease
6
Case6: Male, 36 years onset, 45 years diagnosis, 68 years report, France
CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficiency)
HPOsFreeText: Lost ambulation at 54 years, Started invasive ventilation at 52 years, Started ERT given every other week at a dose of 20 mg/kg at 63 years for 56 months, Peak Anti-rhGAA antibodies at 1:51,200, FVC at 0.7/18 (L / % expected), MIP at 9 (cm H2O), MEP at 13 (cm H2O), Time off ventilation stayed constant at 240 min, Total Motor Function Measure from 49 to 35, 6MWT from 50 to 10 meters
CaseNotHPOs: HP:0030148 (Heart murmur)
NotHPOsFreeText: No adverse reaction to ERT was recorded
CaseAddInfo: Late Onset Pompe Disease, Patient died before publication
PD25
Patient25: Male, Southern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: c.971dupC (p.Ser325GlufsX5) no ClinVar or CAID
Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)
ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/
gnomAD: n/a
PD10
Patient10: Male, Southern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)
ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/
gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A
Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)
ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/
gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C
The patient is a 59-year-old Japanese female
Case: Female, 59yo, Japanese, non-consanguineous family
CasePresentingHPOs: HP:0002515, HP:0001290, HP:0009055, HP:0002015, HP:0002098, HP:0002315, HP:0007340, HP:0004944, HP:0002138, HP:0001297, HP:0000822, HP:0001288, HP:0002788, HP:0003236, HP:0002119, HP:0002415, HP:0012444, HP:0001922, HP:0012529
HPOsFreeText: 3mm aneurysm in left middle cerebral artery, underwent cerebral arterial clipping, muscle atrophy more significant in proximal muscles of lower limbs, hypotonia more significant in right thigh, CPK = 327mg/dL, alanine aminotransferase = 44mg/dL, aspartate aminotransferase = 42mg/dL, lactic dehydrogenase = 266mg/dL, low-density lipoprotein = 162mg/dL, flattened diaphragm, left atrial ventricular enlargement with mass = 156g, left ventricular index = 106g/m^2, extensor muscle atrophy, diffuse fibrosis in thighs, multiple infractions, bilateral tortuous irregular cerebral arteries, GAA activity = 1.3 pmol hour^-1 punch^-1, vacuolated platelets, glycogen accumulation, large lysosomes filled with membrane bound deposition in fibroblasts
CaseNotHPOs: HP:0003691, HP:0012195, HP:0030850, HP:0010535, HP:0000365, HP:0000505, HP:0002111
NotHPOsFreeText: regurgitation
CaseAddInfo: Hypertension developed at 40yo and was treated with antihypertensive drugs. Cerebral stroke at 57yo. Father died at 82yo due to cardiac aneurism and arterial thrombosis. Mother had left ventricular hypertrophy and died at 62yo due to colon carcinoma. Sister had psychiatric illness. Her 2 sons were healthy.
CasePreviousTesting: CT scan, chest x-ray, echocardiogram, MRI, DBS, electron microscopy of blood cells, skin biopsy
CaseGenotypingMethod: PCR and direct DNA sequencing of GAA gene, cDNA-sequencing analysis
Variant: NM_000152.4(GAA):c.546G>T (p.Thr182=), homozygous
ClinVar: 370637, https://www.ncbi.nlm.nih.gov/clinvar/variation/370637/
gnomAD: n/a
P1
PatientF3P1: Female, 3 months diagnosis, Multiracial (maternal European and Native American and paternal Czechoslovakian, German, and Australian)
CasePresentingHPOs: HP:0004755, HP:0001290 (Supraventricular tachycardia, Generalized hypotonia)
CaseAddInfo: Proband
P3
PatientF3P3: Male, 6 years report, Multiracial (maternal European and Native American and paternal Czechoslovakian, German, and Australian)
CaseAddInfo: Presymptomatic, sibling of F3P1 and child of F3P2, has a presymptomatic sister age 4, F3P4, with the same GAA mutations, Author states variants are in trans
7
Patient7: Male, 3.8mo at ERT start, 3.3yo at study end
CasePresentingHPOs:
HPOsFreeText: treated with 40mg/kg/wk, patient had 10 infusion associated reactions
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: 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
Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)
ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
4
Patient4: Male, 2.2mo at ERT start, 1.7yo at study end
CasePresentingHPOs:
HPOsFreeText: treated with 20mg/kg/2wks, patient had 3 infusion associated reactions
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: 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
Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)
ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/
gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C
4
Patient4: 19yo
CasePresentingHPOs:
HPOsFreeText: hyperCKemia, GAA = 24%, BMI = 26.1, normal CTA and CT
CaseNotHPOs:
NotHPOsFreeText: No cardiovascular risk
CaseAddInfo: 12yr disease duration
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1771C>T (p.Arg591Trp)
ClinVar: 551782, https://www.ncbi.nlm.nih.gov/clinvar/variation/551782/
gnomAD: 8.662e-06, http://exac.broadinstitute.org/variant/17-78086393-C-T
14
Patient14: 48yo
CasePresentingHPOs: HP:0003325, HP:0002093, HP:0004944
HPOsFreeText: GAA = 6.5%, BMI = 20.3, MCA M1 tract aneurysm (2mm), normal CT
CaseNotHPOs:
NotHPOsFreeText: No cardiovascular risk
CaseAddInfo: 28yr 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: NC_000017.11:g.(?80118193)(80118357_?)del
ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/
gnomAD: n/a
PD/Pathogenic-9
CasePD/Pathogenic-9: 3 weeks diagnosis
HPOsFreeText: GAA activity 8.4 (nmol · h−1 · mg−1), Mean percentage of normal 11.7%
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.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: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis
LOPD-16
CaseLOPD-16: 2.5 weeks diagnosis
HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%
GenotypingMethod: Newborn Screening Panels
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.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
PD/VOUS-4
CasePD/VOUS-4: 2 weeks diagnosis
HPOsFreeText: GAA activity 5.3 (nmol · h−1 · mg−1), Mean percentage of normal 7.5%
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
20 mg/kg (N = 16)
Case10HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.2 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.1548G>A (p.Trp516Ter)
ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/
gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 https://gnomad.broadinstitute.org/variant/17-78084636-G-A
CaseAddInfo: Patient is compound heterozygous for this variant
20 mg/kg (N = 16)
Case22HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 7 mU/U hexosaminidas, GAA activity at 25% 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.2608C>T (p.Arg870Ter)
ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/
gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 https://gnomad.broadinstitute.org/variant/17-78092118-C-T
CaseAddInfo: Patient is compound heterozygous for these variants
10 mg/kg (N = 3)
Case6HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 1 pmol/punch/hr, GAA activity at 10% 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:
3
Case3: Female, 18 years onset, 19 years diagnosis, 26 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
6
Case6: Female, 22 years onset, 23 years diagnosis, 37 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
9
Case9: Male, 21 years onset, 21.5 years diagnosis, 38 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness, Scapula alata)
CaseAddInfo: Late-Onset Pompe Disease
15
Case15: Male, 3.5 years onset, 5 years diagnosis, 16 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
7
Case7: Male, 11 years onset, 16 years diagnosis, 27 years report
CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
25/F
Patient25: Female
CasePresentingHPOs: HP:0004887
HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, tracheostomy, able to sit independently
CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365
NotHPOsFreeText: infusion associated reaction
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.784G>A (p.Glu262Lys)
ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/
gnomAD: 0.00001417, http://gnomad.broadinstitute.org/variant/17-78081447-G-A
28/M
Patient28: Male
CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365, HP:0001371
HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = 1:3200, infusion associated reaction, tracheostomy, heart normalization
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 4yo, ERT at 9yo
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2237G>A (p.Trp746Ter)
ClinVar: 280063, https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: 0.000003988, http://gnomad.broadinstitute.org/variant/17-78090814-G-A
Variant2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)
ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/
gnomAD: 0.00003188, http://gnomad.broadinstitute.org/variant/17-78085800-T-C
16/M
Patient16: male
CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0001371, HP:0001025
HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:102.400, immunomodulation, infusion associated reaction, tracheostomy, partial heart normalization
CaseNotHPOs: HP:0000365
CaseAddInfo: variants in trans, symptom onset at birth, diagnosis at 3 days, ERT at 4 days
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.2237G>A (p.Trp746Ter)
ClinVar: 280063, https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: 8.301e-06, http://exac.broadinstitute.org/variant/17-78090814-G-A
23/F
Patient23: Female
CasePresentingHPOs: HP:0000365
HPOsFreeText: CRIM positive, heart normalization, moderate periventricular white matter abnormalities (hypomyelination)
CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0002546, HP:0001371
Not HPOsFreeText: infusion associated reaction
CaseAddInfo: homozygous variants in trans, symptom onset at birth, diagnosis and ERT at 1yo
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1933G>A (p.Asp645Asn)
ClinVar: 188728, https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/
gnomAD: 0.000008250, http://gnomad.broadinstitute.org/variant/17-78086719-G-A
11/M
Patient11: male
CasePresentingHPOs: HP:0002546, HP:0001371
HPOsFreeText: CRIM positive, heart normalization, moderate periventricular white matter abnormalities (hypomyelination)
CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0000365
CaseAddInfo: variants in trans, symptom onset at birth, diagnosis at 12 days. Died at 78mo due to cardiorespiratory failure.
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1942G>A (p.Gly648Ser)
ClinVar: 188902, https://www.ncbi.nlm.nih.gov/clinvar/variation/188902/
gnomAD: 0.0001018, http://exac.broadinstitute.org/variant/17-78086728-G-A
Variant2: NM_000152.4(GAA):c.2646+2T>A
ClinVar: 188924, https://www.ncbi.nlm.nih.gov/clinvar/variation/188924/
gnomAD: n/a
P7
Patient7: Male, 4.5mo at diagnosis and ERT
CasePresentingHPOs:
HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 3.5, Glycogen = 31.4 Vv(PAS + /mf)%, larger empty vacuoles = 38.1 Vv (LEV/mf)%, Autophagic vacuoles = 0,06 %/mf
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: homozygous, biopsy taken from musculus vastus lateralis
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.5(GAA):c.2078dup(p.Ala694Glyfs)
ClinVar: 180143, https://www.ncbi.nlm.nih.gov/clinvar/variation/180143/
gnomAD: n/a
P8
Patient8: Male, 1mo at diagnosis, 4mo at ERT
CasePresentingHPOs:
HPOsFreeText: classic IOPD, poor response to ERT, Pompe muscle pathology score = 3.5, Glycogen = 28.4 Vv(PAS + /mf)%, larger empty vacuoles = 46.8 Vv (LEV/mf)%, Autophagic vacuoles = 0,2 %/mf
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: homozygous, biopsy taken from musculus vastus lateralis
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
2
CaseVI,2: Adult onset, 61 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Abnormal respiration, Easy fatiguability, Increased serum CK, Myopathy)
HPOsFreeText: GAA activity from dried blood spot: 0.22%, Forced Vital Capacity Seated: 2040 (46%), 6-Minute Walking Test: 418 min, Plasma CK 2.5-5x Normal
CaseAddInfo: Late-Onset Pompe Disease
1
CaseVI,1: Early adult onset, 63 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003327, HP:0002795, HP:0003388, HP:0003326 (Proximal muscle weakness, Axial muscle weakness, Abnormal respiration, Easy fatiguability, Myalgia)
HPOsFreeText: GAA activity from dried blood spot: 0.24%, Forced Vital Capacity Seated: 1520 (38%)
CaseNotHPOs: HP:0003236 (Increased serum CK)
CaseAddInfo: Late-Onset Pompe Disease
VII
CaseVII: Adolescent onset, 33 years diagnosis
CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002460, HP:0003394 (Proximal muscle weakness, Increased serum CK, Distal muscle weakness, Muscle cramps)
HPOsFreeText: GAA activity from dried blood spot: 0.20%, Forced Vital Capacity Seated: 5260 (112%), Plasma CK 2.5-5x Normal, Vacuoles in histology
CaseNotHPOs: HP:0002795 (Abnormal respiration)
CaseAddInfo: Late-Onset Pompe Disease
1
Patient1: Italian
CasePresentingHPOs:
HPOsFreeText: non-classic IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: homozygous
CasePMIDs:
CasePreviousTesting:
CaseGenotypingMethod: method not described
Variant: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)
ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/
gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C
6a
Family 6 - Patients 6a and 6b
FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0200136, HP:0003691, HP:0003306, HP:0002650, HP:0040081, HP:0002111, HP:0100284
HPOsFreeText: myopathic muscle unit action potentials, 6a muscle pathology with vacuolar myopathy with glycogen excess
FamilyNotHPOs: HP:0010628
Ethnicity: Iranian
ProbandLabel: 6a, male, 12yo at onset, 25yo at diagnosis
FamilyAddInfo: 6b (male) dx at 33yo, 6a MRC sum score = 78, 6b MRC sum score = 79, both patients required use of NIV
FamilyPreviousTesting: Respiratory Evaluation: 6a FVC = 19%, 6b FVC = 38%, 6a CK = 820 U/L, 6b CK = 503 U/L, muscle pathology (examined only in 6a), DBS enzyme activity (with inhibition) for 6a = 0 μmol/L/h, for 6b = 0.21 μmol/L/h, NCS, EMG
FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening
Variant: NM_000152.4(GAA):c.1979G>A (p.Arg660His)
ClinVar: 189172, https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/
gnomAD: 3.279e-05, http://exac.broadinstitute.org/variant/17-78086765-G-A
7
Family 7 - Patient 7
FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0003306, HP:0002111, HP:0040081
HPOsFreeText: muscle pathology with vacuolar myopathy with glycogen excess, myopathic muscle unit action potentials
FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003691, HP:0002650
Ethnicity: Iranian
ProbandLabel:
FamilyAddInfo: male, 20yo at onset, 23yo at diagnosis, MRC sum score = 96, patient required use of NIV
FamilyPreviousTesting: Respiratory Evaluation: FVC = 20%, CK = 2,550 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 0.1 μmol/L/h, NCS, EMG
FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening
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: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
1
Family 1 - Patient 1
FamilyPresentingHPOs: HP:0002355, HP:0003701, HP:0040081, HP:0100284
HPOsFreeText: myopathic muscle unit action potentials
FamilyNotHPOs HP:0010628, HP:0002015, HP:0003691, HP:0003306, HP:0002650
NotHPOsFreeText:
Ethnicity: Iranian
ProbandLabel: Patient 1, male
FamilyAddInfo: 2yo at onset, 4yo at diagnosis, MRC sum score not available, consanguineous family
FamilyPreviousTesting: Respiratory evaluation: FVC = 90%, CK = 2,960 U/L,DBS enzyme activity (with inhibition) = 0.3 μmol/L/h, no muscle pathology performed, cardiac evaluations, NCS, EMG
FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening
Variant: NM_000152.4(GAA):c.854C>G (p.Pro285Arg)
ClinVar: 225114, https://www.ncbi.nlm.nih.gov/clinvar/variation/225114/
gnomAD: n/a
7
Case7: Female, 37 years onset, 38 years diagnosis, Italy
HPOsFreeText: See Group Phenotypes, ERT started at 40, GAA Activity at ~4.5 pmol/min/mg before ERT and ~5.5 after
GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing
Variant1: NM_000152.4:c.-32-13T>G
ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4:c.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
16
Case#: Patient 16, female
CasePresentingHPOs: HP:0003325
CaseAddInfo: onset and diagnosis at 32yo
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
12
Case#: Patient 12, male
CasePresentingHPOs: HP:0003236
CaseAddInfo: 42yo at onset, 46yo 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: NM_000152.4(GAA):c.1438-2A>G
ClinVar: 526521, https://www.ncbi.nlm.nih.gov/clinvar/variation/526521/
gnomAD: n/a
3
Case#: Patient 3, female
CasePresentingHPOs: HP:0003236
CaseAddInfo: 29yo at onset, 39yo 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: 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
17
Case#: Patient 17, female
CasePresentingHPOs: HP:0003236
CaseAddInfo: 38yo at onset, 39yo 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: NM_000152.4(GAA):c.2237G>A (p.Trp746Ter)
ClinVar: 280063, https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: 8.301e-06, http://exac.broadinstitute.org/variant/17-78090814-G-A
11
Patient11: Female, 39yo at diagnosis, 53yo at ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:400, enzyme (μmol/g/h) = 0.41 (3-20), NIV required only after ERT began, mobility aid required before and after ERT
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: 21yr disease duration, variants in trans
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.1548G>A (p.Trp516Ter)
ClinVar: 189025, https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/
gnomAD: n/a
Variant2: NM_000152.4(GAA):c.2799+4A>G
ClinVar: 286228, https://www.ncbi.nlm.nih.gov/clinvar/variation/286228/
gnomAD: 8.319e-06, http://exac.broadinstitute.org/variant/17-78092608-A-G
10a
Patient10: Male, 45yo at diagnosis, 58yo at ERT
CasePresentingHPOs:
HPOsFreeText: anti rh-GAA antibodies titre = 1:3200, enzyme (μmol/g/h) = 0.39 (3-20), mobility aid required before and after ERT
CaseNotHPOs:
NotHPOsFreeText: NIV not required
CaseAddInfo: 27yr 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
7
Patient7: female, Serbian
CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325
HPOsFreeText: CK < 10x increase
CaseNotHPOs: HP:0002093
CaseAddInfo: onset in middle age
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant 1: NM_000152.4(GAA):c.2269C>T (p.Gln757Ter)
ClinVar: 429727, https://www.ncbi.nlm.nih.gov/clinvar/variation/429727/
gnomAD: n/a
Variant2: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: A79V
Variant1ClinVarID: 1458769
Variant1CAID: CA356987
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: H33Q
Variant1ClinVarID: 2134405
Variant1CAID: CA355945479
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: R89W
Variant1ClinVarID: 580286
Variant1CAID: CA2801156
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: A75T
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: G51D
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: Y76C
Variant1ClinVarID: 552686
Variant1CAID: CA2801140
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts
PMID: 34192316
Gene: IDUA
Disease: MPS1
Inheritance: AR
InsufficientEvidence: Study used fibroblasts from patients with MPS-1. Protein changes associated with the variants in the fibroblasts are provided, but no other patient details are provided.
38/M
Case#: Patient 38, male, Han origin, 5 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Airway obstruction (HP:0001263, HP:0006536)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.236C>T (p.A79V)
Variant1ClinVarID: 1458769
Variant1CAID: CA356987
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
22/M
Case#: Patient 22, male, Han origin, 1 year 8 months old (age at diagnosis)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.8 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.236C>T (p.A79V)
Variant1ClinVarID: 1458769
Variant1CAID: CA356987
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed by parental testing.
PreviouslyPublished N/A
18/F
Case#: Patient 18, female, Han origin, 1 year 6 months old (age at diagnosis)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: Hepatosplenomegaly, Hernia (HP:0001433, HP:0100790)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 0.6 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.2T>C (p.Met1Thr)
Variant1ClinVarID: 639529
Variant1CAID: CA2801095
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
4/F
Case#: Patient 4, female, Han origin, 3 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Airway obstruction (HP:0001263, HP:0006536)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.0 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.296+4G>A, it looks like this is a typo and should be c.299+4G>A
Variant1ClinVarID: N/A
Variant1CAID: CA2669476183
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
37/M
Case#: Patient 37, male, Han origin, age at diagnosis not available
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.2T>C (p.Met1Thr)
Variant1ClinVarID: 639529
Variant1CAID: CA2801095
Variant2: c.2T>C (p.Met1Thr)
Variant2ClinVarID: 639529
Variant2CAID: CA2801095
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed by parental testing.
PreviouslyPublished N/A
52/F
Case#: Patient 52, female, Han origin, 2 years old (age at diagnosis)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 1.1 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1210G>T (p.E404X)
Variant1ClinVarID: 552095
Variant1CAID: N/A
Variant2: c.1877G>A (p.W626X)
Variant2ClinVarID: 928997
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
17/M
Case#: Patient 17, male, Han origin, 15 years old (age at diagnosis)
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: Joint stiffness (HP:0001387)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.1 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.236C>T (p.A79V)
Variant1ClinVarID: 1458769
Variant1CAID: CA356987
Variant2: c.265C>T (p.R89W)
Variant2ClinVarID: 580286
Variant2CAID: CA2801156
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
30/M
Case#: Patient 30, male, Han origin, 37 years old (age at diagnosis)
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: Joint stiffness, Airway obstruction (HP:0001387, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0001263, HP:0000256, HP:0011369, HP:0001433, HP:0100790)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 2.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.265C>T (p.R89W)
Variant1ClinVarID: 580286
Variant1CAID: CA2801156
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
54/M
Case#: Patient 54, male, Han origin, age of diagnosis not available
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 0.6 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.236C>T (p.A79V)
Variant1ClinVarID: 1458769
Variant1CAID: CA356987
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 5, 9 years old, Iranian
DiseaseAssertion: MPS1-H/S (Intermediate)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity not detected
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 10, 10 years old, Iranian
DiseaseAssertion: MPS1-S (Attenuated)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.45 µmol/g.h (Normal ranges: 10-50 µmol/g.h)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.152G>A (p.G51D)
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: Unknown
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 8, 5 years old, Iranian
DiseaseAssertion: MPS1-S (Attenuated)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.04 µmol/g.h (Normal ranges: 10-50 µmol/g.h)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
8/m
Case#: Patient 8, female, 4.9 months (age at diagnosis), 8.6 months (age at HSCT), 6.7 - 9.5 months (age at ERT), 4 MRI + neuropsychological observations over the course of 6 years.
DiseaseAssertion: MPS-1H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 28.7 nmol/h/mg (Normal values: 11-43 nmol/h/mg)
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: Yes, transplanted with an unrelated cord blood unit.
Variant1: c.152G>A (p.G51D)
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: c.152G>A (p.G51D)
Variant2ClinVarID: 193061
Variant2CAID: CA274902
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient #4 (see Table 2), male, 2 years old (age at diagnosis), 7 years old (age at report)
DiseaseAssertion: MPS-I
FamilyInfo: Born to a consanguineous marriage.
CasePresentingHPOs: Failure to thrive, short stature, macroglossia, poor eyesight, hearing impairment, scoliosis, developmental delay (HP:0001508, HP:0004322, HP:0000158, HP:0000505, HP:0000365, HP:0002650, HP:0001263)
CaseHPOFreeText: Extra abnormal body and abdominal inflammation
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: α-L-iduronidase 6.4 pmol/spot. The activity of this enzyme is below its reference (350–2600 pmol/spot)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient #5 (see Table 2), female, 1 year old (age at diagnosis), 3 years old (age at report)
DiseaseAssertion: MPS-I
FamilyInfo: Born to a consanguineous marriage
CasePresentingHPOs: Coarse facial features, macroglossia, developmental delay, failure to thrive, skeletal dysplasia (HP:0000256, HP:0000158, HP:0001263, HP:0001508, HP:0002652)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: α-L-iduronidase 1.5 pmol/spot. The activity of this enzyme is below its reference (200–2600 pmol/spot)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Abnormal
Case#: No additional case information provided
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Abnormal
CaseUrineGAGs: Abnormal
CaseERT: N/A
CaseBMT: N/A
Variant1: c.250G>A (p.G84S)
Variant1ClinVarID: 726495
Variant1CAID: CA2801152
Variant2: c.250G>A (p.G84S)
Variant2ClinVarID: 726495
Variant2CAID: CA2801152
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
103
Case#: Pt 103 , Age 19 years, Female, DiseaseAssertion: MPS1 Scheie syndrome. FamilyInfo: NA CasePresentingHPOs: NA CaseHPOFreeText: NA CaseNotHPOs: NA CaseNotHPOFreeText: NA
CaseEnzymeAssay: Low leukocyte IDUA enzyme activity CaseUrineGAGs: NA CaseERT: No CaseBMT: No Variant1: IVS7+1G>A This may be the variant c.972+1G>A, though cDNA not mentioned in text. Variant1ClinVarID: 198406 Variant1CAID: Variant2:p.X654R , cDNA not mentioned This variant may result from prev reported c.1960T>C ( ClinVar 960079) or from c.1960T>G ( ClinVar 11920) Variant2ClinVarID: Variant2CAID: AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA
102
Case#: Pt 102 , Age 37 years, Female, DiseaseAssertion: MPS1 Scheie syndrome. FamilyInfo: NA CasePresentingHPOs: NA CaseHPOFreeText: NA CaseNotHPOs: NA CaseNotHPOFreeText: NA
CaseEnzymeAssay: Low leukocyte IDUA enzyme activity CaseUrineGAGs: NA CaseERT: No CaseBMT: No Variant1: p.Q70X Variant1ClinVarID: 11909 Variant1CAID: CA204563 Variant2:p.D445del Variant2ClinVarID: 840115 Variant2CAID: AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA
205
Case#: 205 5 yrs male, age at initial diagnosis 1.1 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 1.5 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months
CaseBMT: No PreviouslyPublished Don't know Variant1:l Variant1: c.494-1G>A ClinVarID: 557942 Variant1CAID: Variant2:c.494-1G>A Variant2ClinVarID: 557942 Variant2CAID:
Hurler disease
Case#: Patient 4, 9 months old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 1.6% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.Ala75Thr)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.223G>A (p.Ala75Thr)
Variant2ClinVarID: 222993
Variant2CAID: CA356994
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 3, 1 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures (HP:0000280, HP:0001433, HP:0002828)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.5% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.Ala75Thr)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.223G>A (p.Ala75Thr)
Variant2ClinVarID: 222993
Variant2CAID: CA356994
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 1, 1 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0001249)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.1% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.152G>A (p.Gly51Asp)
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: c.152G>A (p.Gly51Asp)
Variant2ClinVarID: 193061
Variant2CAID: CA274902
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 2, 5 months old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, corneal clouding, recurrent infections, intellectual disability (HP:0000280, HP:0007957, HP:0002719, HP:0001249)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.203G>A (p.Trp68Ter)
Variant1ClinVarID: 2734634
Variant1CAID: CA2801137
Variant2: c.203G>A (p.Trp68Ter)
Variant2ClinVarID: 2734634
Variant2CAID: CA2801137
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.251G>C
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.251G>C (p.G84A)
Variant1ClinVarID: 2203494
Variant1CAID: CA355946494
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.299G>A
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.299G>A (p.R100K)
Variant1ClinVarID: 281005
Variant1CAID: CA2801160
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.223G>A
Case#: Functional assay variant with a clinical significance of pathogenic.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.A75T)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.250G>A
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.250G>A (p.G84S)
Variant1ClinVarID: 726495
Variant1CAID: CA2801152
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
5
Case#: Patient 5, male, 1 year and 6 months (age at presentation)
DiseaseAssertion: MPS1-H/S
FamilyInfo: Consanguinity in the family present for this patient.
CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint contractures, extensive Mongolian spots (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0100790, HP:0011369)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.A75T)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.223G>A (p.A75T)
Variant2ClinVarID: 222993
Variant2CAID: CA356994
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3
Case#: Patient 3, male, 1 year (age at presentation)
DiseaseAssertion: MPS1-H
FamilyInfo: Consanguinity in the family present for this patient.
CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hydrocephalus, intellectual disability, extensive Mongolian spots (HP:0007957, HP:0000256, HP:0000943, HP:0000238, HP:0010864, HP:0011369)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.A75T)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.223G>a (p.A75T)
Variant2ClinVarID: 222993
Variant2CAID: CA356994
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4
Case#: Patient 4, female, 2 years and 3 months (age at presentation)
DiseaseAssertion: MPS1-H
FamilyInfo: Consanguinity in the family present for this patient.
CasePresentingHPOs: Coarse facial features, dysostosis multiplex, hepatomegaly, splenomegaly, intellectual disability (HP:0000256, HP:0000943, HP:0002240, HP:0001744, HP:0010864)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>A (p.A75T)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.223G>A (p.A75T)
Variant2ClinVarID: 222993
Variant2CAID: CA356994
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Patient offamily A
Case#: Patient 1 of family A: Enrolled in study at 16 months, male, DiseaseAssertion:MPS1 FamilyInfo:Consanguinity Yes CasePresentingHPOs: Asthma HP:0002099, Sleep apnea HP:0010535, Multiple joint contractures HP:0002828, Kyphosis HP:0002808, Recurrent ear infections HP:0410018, Coarse facial features HP:0000280, Hepatosplenomegaly (HP:0001433), Inguinal hernia HP:0000023 Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), CaseHPOFreeText: nose/throat infections, aggressive, heavy eye brows, large tongue, thick lips , rough skin CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: enzyme values lower than the cut-off values CaseUrineGAGs: NA CaseERT: NA CaseBMT:Nil Variant1:c.1456G>T ,Glu486 Variant1ClinVar ID: 651168 Variant1CAID: Variant2:c.1456G>T ,Glu486 Variant2ClinVarID:651168 Variant2CAID: AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA
a female of Italian descent identified in 2018 (currently 2 years old) is compound heterozygous for two mutations with severe phenotypes (c.46_57del12/p.Y201X)
Case#: P2 (IDUA-02)
DiseaseAssertion: MPS1
FamilyInfo: None provided
CasePresentingHPOs:No info
CaseHPOFreeText: No info
CaseNotHPOs: No info
CaseNotHPOFreeText: No info
CaseEnzymeAssay: Newborn screening using dried blood spot by stable isotope dilution flow injection MS/MS %IDUA enzyme activity =0.17 microM/hour
CaseUrineGAGs: Confirmatory testing using urinary GAGs (heparan [HS] and dermatan sulfate [DS] by LS-MS/MS method: DS=1.79 mg/L, HS=0.77 mg/L
CaseERT: Started ERT (100 U/kg/Week) withing 15 days of birth
CaseBMT: No info
Variant1:c.46_57del12
Variant1ClinVarID:92643
Variant1CAID:
Variant2: p.Y201X
Variant2ClinVarID:1323100
Variant2CAID:
AdditionalVariants:
ParentalGenotype: No info
PreviouslyPublishedNot stated
Q60X
Case#: Family 10, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.178C>T (p.Q60X)
Variant2ClinVarID: 655054
Variant2CAID: CA355946098
AdditionalVariants: N/A
ParentalGenotype: Parental testing conducted, each parent was shown to carry one of the sequence changes found in their affected child.
PreviouslyPublished N/A
Case#: Patient 8, 5 years old, Iranian
DiseaseAssertion: MPS1-S (Attenuated)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.04 µmol/g.h (Normal ranges: 10-50 µmol/g.h)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 5, 9 years old, Iranian
DiseaseAssertion: MPS1-H/S (Intermediate)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity not detected
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 10, 10 years old, Iranian
DiseaseAssertion: MPS1-S (Attenuated)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.45 µmol/g.h (Normal ranges: 10-50 µmol/g.h)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.152G>A (p.G51D)
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: Unknown
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Patient 2
Case#: 2, Male, 4 years 4 months (diagnosed), 17 years (report), weight at presentation : NA, Height at presentation NA, Born in Uruguay
Disease Assertion: Hurler Scheie ( attenuated phenotype)
FamilyInfo: Parents are not consanguineous
Case Presenting HPOs: HP: 0002808, HP: 0002937, HP: 0000280, HP:0000470, HP:0001376, HP:0034337, HP: 0000768, HP:0000943 (Kyphosis, Hemivertebrae, Coarse face, Short neck, Limitation of joint mobility, claw hands, pectus carinatum, dysostosis multiplex )
CaseHPOFreeText: Bony dysplasia
CaseNotHPOs: HP:0007957 HP:0001249, HP:0001433, ( Corneal opacity , Intellectual disability , visceromegaly)
CaseNotHPOFreeText:
CaseEnzymeAssay: IDUA enzyme in dried blood spot 0.26 nmol/h/L ( 2.20-11.70 )
CaseUrineGAGs: NA CaseERT: N/A
CaseBMT: N/A
Genotyping Method: Sanger Sequencing
Variant1: p.L18P (c.53C>T)
Variant1ClinVarID: 193062
Variant1CAID: NA
Variant2: p.W402X
Variant2ClinVarID: 11908
Variant2CAID: 220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
c.1A>C
Case#: No individual patient information available. 11/59 patients studied (18.7%) had this variant. This variant originates from two regions of Iran. 5 patients came from the city of Rasht in the Gilan province, making it a focal point for this variant. 6 patients came from five different provinces in the southwestern regions of Iran.
DiseaseAssertion: MPS1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished This variant has previously been reported in studies conducted by Atceken et al. (2016) and Bertola et al. (2011), in patients from Turkey and Spain respectively. However, there has been no report suggestive of a founder effect for this variant.
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:int3 -2a>g
Variant1ClinVarID:
Variant1CAID:
Variant2:L238Q
Variant2ClinVarID:265418
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:L238Q
Variant1ClinVarID:265418
Variant1CAID:
Variant2:W402X
Variant2ClinVarID:
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:L238Q
Variant1ClinVarID:265418
Variant1CAID:
Variant2:63delC
Variant2ClinVarID:
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:65delC
Variant1ClinVarID:
Variant1CAID:
Variant2:H240R
Variant2ClinVarID:947028
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Case#: Pt 8, age is 8 months (proband can be found in Table 1)
DiseaseAssertion: Hurler syndrome, mucopolysaccharidosis type IH, MPS IH, MPS type I
FamilyInfo: No family information provided
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: In methods it is stated that an IDUA activity assay was conducted on cartilaginous pellets generated from patient-derived bone marrow stromal cells at 5 weeks. However, results of the IDUA activity assays are not stated.
CaseUrineGAGs: "Significantly higher levels of GAGs in MPS IH compared with HD pellets at.1 week of chondrogenic differentiation, thus indicating that GAG accumulation in MPS IH can be seen during cell condensation and early differentiation stages." Total GAG content for each sample in ug GAG/ug DNA shown in Figure 4 graphs.
CaseERT: Don't know
CaseBMT: Don't know
Variant1: p.G51D
Variant1ClinVarID: 193061
Variant1CAID: CA274902
Variant2: p.G51D
Variant2ClinVarID: 193061
Variant2CAID: CA274902
AdditionalVariants: No additional variants mentioned
ParentalGenotype: No parental information provided
PreviouslyPublished: No mention of being previously published
patient with MPS
Case#: No case information provided
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Exact number not stated but "significantly decreased".
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.2T>C (p.M1?)
Variant1ClinVarID: 639529
Variant1CAID: CA2801095
Variant2: c.2T>C (p.M1?)
Variant2ClinVarID: 639529
Variant2CAID: CA2801095
AdditionalVariants: N/A
ParentalGenotype: Both parents were identified as carriers of the mutation
PreviouslyPublished N/A
Case#: Patient 1, Turkish
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.1A>C (p.M1L)
Variant2ClinVarID: 550458
Variant2CAID: CA355945204
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case247: Female, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 36%, LVDD-Z score at -0.244
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history, Heart transplant required
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.2135G>A (p.Arg712His)
ClinVar: 575575 https://www.ncbi.nlm.nih.gov/clinvar/variation/575575/
gnomAD: Not in gnomAD
DCM-01
CaseDCM-01: Male, 1 year diagnosis, Caucasian, Germany
CasePresentingHPOs: HP:0001644, HP:0001635 (Dilated cardiomyopathy, Heart failure)
HPOsFreeText: LVEDD at 67 mm, LV-Ejection Fraction at 10%, Cardiac Index at 2.6
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Proband treated with VAD and HTx, No family history of cardiac disease, MYH7 Variant is asserted as de novo, Proband also has a variant in MYL2, Patient is heterozygous for MYH7 variant
CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.
Variant: NM_000257.3:c.5390T>C (p.Leu1797Pro)
ClinVar: 265799 https://www.ncbi.nlm.nih.gov/clinvar/variation/265799/
gnomAD: Not in gnomAD
Multiple Gene Variants
MYL2 Variant
Variant: NM_000432.3:c.401A>C (p.Glu134Ala)
ClinVar: 43475 https://www.ncbi.nlm.nih.gov/clinvar/variation/43475/
gnomAD: European (Non-Finnish) 3.484e-4, Overall 2.015e-4 https://gnomad.broadinstitute.org/variant/12-111350901-T-G
ARVC-02
CaseARVC-02: Male, 35 year diagnosis, Caucasian, Germany
CasePresentingHPOs: HP:0011663, HP:0001635 (Right ventricular cardiomyopathy, Heart failure)
HPOsFreeText: RVEDD at 61 mm
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Proband treated with HTx and ICD, Father died of cardiac issues, Brother has heart disease, Patient is heterozygous for MYH7 variant
CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.
Variant: NM_000257.3:c.3715A>G (p.Ile1239Val)
ClinVar: 265831 https://www.ncbi.nlm.nih.gov/clinvar/variation/265831/
gnomAD: Not in gnomAD
CaseMYH7-23: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2225C>A (p.Ala742Glu)
ClinVar: 192310 https://www.ncbi.nlm.nih.gov/clinvar/variation/192310/
gnomAD: Not in gnomAD
WJ
CaseWJ: 30 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: One affected relative Brother (index case) died suddenly aged 34 y (MYH7 p.Asp778Val only)
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: Maximum left ventricular hypertrophy at 18 mm
CaseNotHPOs: N/A
NotHPOsFreeText: Sudden cardiac death event
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant1: NM_000257.3:c.2333A>T (p.Asp778Val)
ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/
gnomAD: Not in gnomAD
Variant2: NM_000257.3:c.5452C>T (p.Arg1818Trp)
ClinVar: 217826 https://www.ncbi.nlm.nih.gov/clinvar/variation/217826/
gnomAD: Latino 5.782e-5, Overall 7.956e-6 https://gnomad.broadinstitute.org/variant/14-23884311-G-A
CaseMYH7-12: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.3236G>A (p.Arg1079Gln)
ClinVar: 177826 https://www.ncbi.nlm.nih.gov/clinvar/variation/177826/
gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.073e-6 https://gnomad.broadinstitute.org/variant/14-23891398-C-T
CaseMYH7-8: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.4075C>T (p.Arg1359Cys)
ClinVar: 178082 https://www.ncbi.nlm.nih.gov/clinvar/variation/178082/
gnomAD: European (Non-Finnish) 8.793e-6, Overall 7.954e-6 https://gnomad.broadinstitute.org/variant/14-23887513-G-A
CaseMYH7-22: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2333A>T (p.Asp778Val)
ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/
gnomAD: Not in gnomAD
CaseMYH7-19: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2539A>G (p.Lys847Glu)
ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/
gnomAD: Not in gnomAD
AJV
CaseAJV: 17 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.
CasePresentingHPOs: HP:0001639, HP:0006536 (Hypertrophic cardiomyopathy, Obstructive lung disease)
HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1954A>G (p.Arg652Gly)
ClinVar: 177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/
gnomAD: Not in gnomAD
Multiple Gene Variants:
MYBPC3 Variant
Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)
ClinVar: 180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/
gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A
CaseMYH7-11: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.3325A>G (p.Lys1109Glu)
ClinVar: 492984 https://www.ncbi.nlm.nih.gov/clinvar/variation/492984/
gnomAD: Not in gnomAD
CaseMYH7-10: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.3592G>T (p.Asp1198Tyr)
ClinVar: 520451 https://www.ncbi.nlm.nih.gov/clinvar/variation/520451/
gnomAD: Not in gnomAD
CaseMYH7-31: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 1 other proband shares this genotype
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.1954A>G (p.Arg652Gly)
ClinVar: 177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/
gnomAD: Not in gnomAD
CaseMYH7-18: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.2578A>G (p.Lys860Glu)
ClinVar: 192312 https://www.ncbi.nlm.nih.gov/clinvar/variation/192312/
gnomAD: Not in gnomAD
CaseMYH7-2: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.
Variant: NM_000257.3:c.5287G>A (p.Ala1763Thr)
ClinVar: 177846 https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/
gnomAD: European (Non-Finnish) 1.238e-4, Overall 7.423e-5 https://gnomad.broadinstitute.org/variant/14-23884476-C-T
CaseMYH7-8: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2539A>G (p.Lys847Glu)
ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/
gnomAD: Not in gnomAD
CaseMYH7-27: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.505A>G (p.Arg169Gly)
ClinVar: 177664 https://www.ncbi.nlm.nih.gov/clinvar/variation/177664/
gnomAD: Not in gnomAD
CaseMYH7-5: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2198G>T (p.Gly733Val)
ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/
gnomAD: Not in gnomAD
CasePT-41: 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.3749G>C (p.Arg1250Pro)
ClinVar: 181232 https://www.ncbi.nlm.nih.gov/clinvar/variation/181232/
gnomAD: East Asian 5.437e-5, Overall 7.958e-6 https://gnomad.broadinstitute.org/variant/14-23888796-C-G
CasePT-110: 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.5326A>G (p.Ser1776Gly)
ClinVar: 177629 https://www.ncbi.nlm.nih.gov/clinvar/variation/177629/
gnomAD: East Asian 3.007e-4, Overall 4.595e-5 https://gnomad.broadinstitute.org/variant/14-23884437-T-C
Multiple Gene Variants:
MYBPC3 Variant:
Variant is reported as below, but the nucleotide sequence is incorrect. Unable to register
Variant: NM_000256.3:c.76A>G (p.Ser236Gly)
CasePT-99: 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.4199C>G (p.Ala1400Gly)
ClinVar: 181248 https://www.ncbi.nlm.nih.gov/clinvar/variation/181248/
gnomAD: Not in gnomAD
CasePT-42: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo: 2 other siblings share the same genotype
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.5317C>A (p.Gln1773Lys)
ClinVar: 181277 https://www.ncbi.nlm.nih.gov/clinvar/variation/181277/
gnomAD: Not in gnomAD
CasePT-33: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo: PT-34 is the proband's sibling in Family 17 with the same genotype
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.1615A>G (p.Met539Val)
ClinVar: 181409 https://www.ncbi.nlm.nih.gov/clinvar/variation/181409/
gnomAD: Not in gnomAD
CasePT-30: 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.2606G>A (p.Arg869His)
ClinVar: 177667 https://www.ncbi.nlm.nih.gov/clinvar/variation/177667/
gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894051-C-T
CasePT-76: 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.2334C>G (p.Asp778Glu)
ClinVar: 265252 https://www.ncbi.nlm.nih.gov/clinvar/variation/265252/
gnomAD: Not in gnomAD
CasePT-97: 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.4159G>A (p.Glu1387Lys)
ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/
gnomAD: South Asian 3.266e-5, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23887429-C-T
DiseaseAssertion: Dilated Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, and VCL were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 74 DCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in two DCM probands and relatives
Variant: NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys)
ClinVarID: 181278 https://www.ncbi.nlm.nih.gov/clinvar/variation/181278/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in two HCM probands
Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)
ClinVarID: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one proband
Variant: NM_000257.4(MYH7):c.1324C>T (p.Arg442Cys)
ClinVarID: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/
gnomAD: 0.00005012, http://gnomad.broadinstitute.org/variant/14-23898247-G-A
DiseaseAssertion: Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were all tested in the PanCM panel.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 305 PanCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
VariantAddInfo: Seen in one PanCM proband
Variant: NM_000257.4(MYH7):c.3157C>T (p.Arg1053Trp)
ClinVar: 181382 https://www.ncbi.nlm.nih.gov/clinvar/variation/181382/
gnomAD: Not in gnomAD
DiseaseAssertion: None
VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.
Variant: NM_000257.4(MYH7):c.4668C>A (p.Gly1556=)
ClinVar: 626810 https://www.ncbi.nlm.nih.gov/clinvar/variation/626810/
gnomAD: 0.0009022, http://gnomad.broadinstitute.org/variant/14-23885498-G-T
25
CaseVIII: Brazil, Caucasian
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: Family history of HCM, 1 other relative without phenotypes
CasePresentingHPOs: HP:0001712, HP:0001639, HP:0011103 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Cosegregation confirmed for MYH7
CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.
CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.
Variant: NM_000257.3:c.4402G>A (p.Glu1468Lys)
ClinVar: 235033 https://www.ncbi.nlm.nih.gov/clinvar/variation/235033/
gnomAD: Not in gnomAD
Multiple Gene Variants
MYBPC3 Variant
Variant: NM_000256.3:c.2686G>A (p.Val896Met)
ClinVar: 42652 https://www.ncbi.nlm.nih.gov/clinvar/variation/42652/
gnomAD: European (Finnish) 0.02794, Overall 0.006194 https://gnomad.broadinstitute.org/variant/11-47357479-C-T
HCM4.1
CaseHCM4.1: Mixed ancestry
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0000819 (Diabetes mellitus)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.2282C>A (p.Thr761Asn)
ClinVar: 546292 https://www.ncbi.nlm.nih.gov/clinvar/variation/546292/
gnomAD: Not in gnomAD
2
Case2: Male, 43 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0001639, HP:0001667, HP:0005110 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Atrial fibrillation)
HPOsFreeText: 0 SCD risk factors, NYHA class is II, Right ventricular wall thickness 14.9 mm
CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.
Variant: NM_000257.3:c.2123G>C (p.Gly708Ala)
ClinVar: 42882 https://www.ncbi.nlm.nih.gov/clinvar/variation/42882/
gnomAD: Not in gnomAD
MultipleGeneVariants:
MYBPC3 Variant:
Variant: NM_000256.3:c.1000G>A (p.Glu334Lys)
ClinVar: 177902 https://www.ncbi.nlm.nih.gov/clinvar/variation/177902/
gnomAD: East Asian 3.338e-3, Overall 2.368e-4 https://gnomad.broadinstitute.org/variant/11-47367848-C-T
**TTN Variant
Unknown Variant
Variant: TTN-E23808K
CAID: N/A
gnomAD: N/A
ACTN2 Variant
Unknown Variant
Variant: ACTN2-P32fs
CAID: N/A
gnomAD: N/A
DSC2 Variant
Unknown Variant, as 3 possible mutations can be responsible for this protein change
Variant: DSC2-S574R
CAID: N/A
gnomAD: N/A
LAMA4 Variant
Unknown Variant
Variant: LAMA4-L1040P
CAID: N/A
gnomAD: N/A
SYNEC2 Variant
Unknown Variant, as 3 possible mutations can be responsible for this protein change
Variant: SYNE2-W5861C
CAID: N/A
gnomAD: N/A
CaseCM1832: Male, 0 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother is negative for this variant
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2609G>T (p.Arg870Leu)
ClinVar: 235031 https://www.ncbi.nlm.nih.gov/clinvar/variation/235031/
gnomAD: Not in gnomAD
CaseCM0969: Male, 6 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Variant is asserted as novel, Both father and sister with HCM tested positive for this variant
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2777T>C (p.Leu926Pro)
ClinVar: 525005 https://www.ncbi.nlm.nih.gov/clinvar/variation/525005/
gnomAD: Not in gnomAD
Case35: Male, 26 years report
HPOsFreeText: ERT not started, 6 Minute Walking Test at 645 meters, Forced Vital Capacity at 101%
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.655G>A (p.Gly219Arg)
ClinVar: 189065 https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: African 4.024e-5, Overall 1.809e-5 http://gnomad.broadinstitute.org/variant/17-78079656-G-A
CaseAddInfo: Late Onset Pompe Disease
Case12: Male, 45 years report
HPOsFreeText: 5 years of ERT completed, 6 Minute Walking Test at 301 meters, Forced Vital Capacity at 13%
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.655G>A (p.Gly219Arg)
ClinVar: 189065 https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/
gnomAD: African 4.024e-5, Overall 1.809e-5 http://gnomad.broadinstitute.org/variant/17-78079656-G-A
CaseAddInfo: Late Onset Pompe Disease
Case17: Female, 49 years report
HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 314 meters, Forced Vital Capacity at 54%
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.1548G>A (p.Trp516Ter)
ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/
gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-G-A
CaseAddInfo: Late Onset Pompe Disease
Case26: Female, 65 years report
HPOsFreeText: 5 years of ERT completed, Forced Vital Capacity at 57%
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.1548G>A (p.Trp516Ter)
ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/
gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-G-A
CaseAddInfo: Late Onset Pompe Disease
Case27: Male, 71 years report
HPOsFreeText: 0.3 years of ERT completed, 6 Minute Walking Test at 348 meters, Forced Vital Capacity at 53%
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.2608C>T (p.Arg870Ter)
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
CaseAddInfo: Late Onset Pompe Disease
Ten patients received concomitant immunomodulation (detailed in Supplementary Table S4); six were genotype-predicted as CRIM-negative, three were CRIM-positive, and one lacked genotype data.
Patient 6
Variant1: NM_000152.4(GAA):c.1292_1295dup (p.Gln433Alafs)
ClinVar: 552165, https://www.ncbi.nlm.nih.gov/clinvar/variation/552165/
gnomAD: 0.000004293, http://gnomad.broadinstitute.org/variant/17-78082592-C-CTGCA
Variant2: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)
ClinVar: 4034, https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/
gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T
Ten patients received concomitant immunomodulation (detailed in Supplementary Table S4); six were genotype-predicted as CRIM-negative, three were CRIM-positive, and one lacked genotype data.
Patient 7:
Variant1: NM_000152.4(GAA):c.1933G>C (p.Asp645His)
ClinVar: 189013, https://www.ncbi.nlm.nih.gov/clinvar/variation/189013/
gnomAD: 0.000008250, http://gnomad.broadinstitute.org/variant/17-78086719-G-C
Variant2: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 0.00001998, http://gnomad.broadinstitute.org/variant/17-78092467-G-T
Ten patients received concomitant immunomodulation (detailed in Supplementary Table S4); six were genotype-predicted as CRIM-negative, three were CRIM-positive, and one lacked genotype data.
Patient 10
Variant1: NM_000152.4(GAA):c.2237G>A (p.Trp746Ter)
ClinVar: 280063, https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/
gnomAD: 0.000003988, http://gnomad.broadinstitute.org/variant/17-78090814-G-A
Variant2: NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs)
ClinVar: 189041, https://www.ncbi.nlm.nih.gov/clinvar/variation/189041/
gnomAD: n/a
A 50-year-old man
Subject II-8: male, 50yo
CasePresentingHPOs: HP:0002094, HP:0002015, HP:0003323, HP:0002878, HP:0006532, HP:0000822, HP:0005978, HP:0003119, HP:0004325, HP:0009055, HP:0012533, HP:0002540, HP:0003698, HP:0030829, HP:0003236, HP:0010899, HP:0003445, HP:0001271
HPOsFreeText: Previously hospitalized 3 times, during the last of which he received a tracheostomy and was dependent on a ventilator. When study began, he was being treated with IV gamma-globulin therapy for likely chronic inflammatory demyelinating polyneuropathy. Motor examination showed symmetrical 2/5 proximal and 4/5 distal strength. Absent reflexes of bilateral biceps, triceps, patellar, and ankle jerk. Allodynia in soles and distal parts of both legs, normal cardiologic examination, bilateral reduced breath sounds, CK = 132 IU/L, aspartate aminotransferase = 46 IU/L, denervation and spontaneous activity with complex repetitive discharges on muscles associated with cranial nerves and cervical, thoracic, and lumbar areas. Demyelinating, mixed sensorimotor polyneuropathy with absent F wave, reduced GAA activity. 6mo after discharge with tracheostomy and ventilator support patient died from respiratory failure due to pulmonary infection.
CaseNotHPOs: HP:0007185, HP:0001291, HP:0003487, HP:0002370, HP:0011675
NotHPOsFreeText: Absent Hoffmann signs, no myotonic phenomenon
CaseAddInfo: Symptoms (dyspnea, dysphagia, and muscle weakness) had been occurring for 2yrs prior to initiation of case study. based on pedigree, it is likely this patients variants are in trans
CasePMIDs:
CasePreviousTesting: neurological examination, motor examination, cardiologic eamination, pulmonary evaluation, lab studies (CK, AST), ECG, needle electromyogram, nerve conduction studies, DBS
CaseGenotypingMethod: genetic analysis (method not described)
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.2560C>T (p.Arg854Ter)
ClinVar: 4034, https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/
gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T
Variant3: NM_000152.4(GAA):c.1551+42G>A
ClinVar: 496841, https://www.ncbi.nlm.nih.gov/clinvar/variation/496841/
gnomAD: 0.003009, http://gnomad.broadinstitute.org/variant/17-78084681-G-A
2/M
Patient2: Male, African American, 11yo
CasePresentingHPOs:
HPOsFreeText: IOPD, rhGAA IgG antibody titer = 800, CRIM positive
CaseNotHPOs:
NotHPOsFreeText: no infusion associated reactions
CaseAddInfo: 15mo at diagnosis, 16mo at ERT start
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.1447G>A (p.Gly483Arg)
ClinVar: 285157, https://www.ncbi.nlm.nih.gov/clinvar/variation/285157/
4/M
Patient4: Male, Caucasian, 12yo
CasePresentingHPOs: HP:0001025 (hives)
HPOsFreeText: IOPD, rhGAA IgG antibody titer = 400, CRIM positive
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo: homozygous, 2.7mo at diagnosis, 2.9mo at ERT start
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant: NM_000152.4(GAA):c.1933G>A (p.Asp645Asn)
ClinVar: 188728, https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/
gnomAD: 0.000008250, https://gnomad.broadinstitute.org/variant/17-78086719-G-A
Detailed characteristics of these patients
Patient6: male, 50yo, adult onset
CasePresentingHPOs:
HPOsFreeText: LOPD, BMI = 26.3 / 26.6 / n-a, required use of wheelchair and BiPAP, WGMS = 3 / 4 / n-a
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.-32-13T>G
Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/
gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G
Variant2: NM_000152.4(GAA):c.1143delC (p.Ala382Leufs)
ClinVar: 370263, https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/
gnomAD: 0.000004031, http://gnomad.broadinstitute.org/variant/17-78082353-AC-A
PD01
Patient1: Female, northern China
CasePresentingHPOs:
HPOsFreeText: IOPD
CaseNotHPOs:
NotHPOsFreeText:
CaseAddInfo:
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)
ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/
gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T
Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)
ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/
1
Case1: 0.2 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: 3442 BNP (pg/ml), 4.71 IVS (d) z score, 4.29 IVS (s) z score, Heart Failure at NYHA Class 3
NotHPOsFreeText: No left-ventricular outflow tract obstruction
CaseAddInfo: Infantile-Onset Pompe Disease
#21
Case21: Female, 5 years onset, 5 years diagnosis
CaseAddInfo: Late-Onset Pompe Disease
30
Case30: Female, 10 yr onset, 11 yr diagnosis, 16.4 yr report
CasePresentingHPOs: HP:0002650 (Scoliosis)
HPOsFreeText: Wheelchair used at 16 yr, Respiratory support used at 12 yr, FVC z-score sitting -8.07 (13% pred), 72% MRC Scale, 1560 CK U/l, 3.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts
15
Case15: Male, 8 yr onset, 4 yr diagnosis, 15.8 yr report
HPOsFreeText: FVC z-score sitting -2.65 (70% pred), FVC z-score supine -3.05 (65% pred), 93% MRC Scale, 1424 CK U/l, 7.8 GAA activity (nmol/h/mg)^h from cultured fibroblasts
NotHPOsFreeText: No wheelchair used, No respiratory support
Patient 3
Case3: Female, Caucasian, United States, 8 days diagnosis, 2 weeks onset, 1.2 years report
CasePresentingHPOs: HP:0003236, HP:0002194, HP:0003749, HP:0003093, HP:0003273, HP:0003184, HP:0008796, HP:0006380, HP:0001435, HP:0003484, HP:0006589, HP:0003725, HP:0008981, HP:0001270, HP:0001290, HP:0002376 (Increased serum CK, Delayed gross motor development, Pelvic girdle muscle weakness, Limited hip extension, Hip flexion contractures, Decreased hip abduction, Externally rotated hips, Knee flexion contracture, Abnormality of the shoulder girdle musculature, Upper limb muscle weakness, Flaring of lower rib cage, Firm muscles, Calf muscle hypertrophy, Motor delay, Generalized hypotonia, Developmental regression)
HPOsFreeText: Had hyperCKemia since the second week of life (605 IU/L, day 8 of life; 513 IU/L, age 3 months), At 5 months she was unable to hold head up to 90 degrees in prone, unable to sit with slight support but unable to prop-sit, and unable to bear weight on hands in prone with AIMS score at the 10th percentile, PT evaluation at age 6 months revealed progression of delay in gross motor milestones, with AIMS score at the 3rd percentile, Unable to sit upright or unsupported and unable to push up on arms in prone, scored only 20% on Dimension B (Sitting) of the GMFM, Imbalanced weakness was evident in trunk and pelvic musculature with predominant active use of, and positioning in, hip flexion/abduction/external rotation in supine, prone and sitting, decreased use of hip extensors and abdominals, and limitation in the use of abdominal obliques for active trunk rotation, Adduction, Tightness in hip flexors, IT bands, and plantar flexors present, Weakness in abdominals, and in hip extension, ankle dorsiflexion, and ankle eversion persisted at 16 months after walking began, ALT 198 U/L (Normal 5–40 U/L), AST 139 U/L (Normal 15–41 U/L), ALP 248 U/L (Normal 24–170 U/L), Urinary Glc4 7.3 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)