Case78

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2608C>T (p.Arg870*)

ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/

gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 http://gnomad.broadinstitute.org/variant/17-78092118-C-T

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case42

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2512C>T (p.Gln838*)

ClinVar: 92479 https://www.ncbi.nlm.nih.gov/clinvar/variation/92479/

gnomAD: African 6.177e-5, Overall 3.997e-6 http://gnomad.broadinstitute.org/variant/17-78092022-C-T

Variant2: NM_000152.4:c.2105G>T (p.Arg702Leu)

CAID: 92472 https://www.ncbi.nlm.nih.gov/clinvar/variation/92472/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case34

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.1942G>A (p.Gly648Ser)

ClinVar: 188902 https://www.ncbi.nlm.nih.gov/clinvar/variation/188902/

gnomAD: South Asian 3.365e-4, Overall 5.361e-5 http://gnomad.broadinstitute.org/variant/17-78086728-G-A

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

Case56

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1796C>A (p.Ser599Tyr)

ClinVar: 551558 https://www.ncbi.nlm.nih.gov/clinvar/variation/551558/

gnomAD: European (Non-Finnish) 2.683e-5, Overall 1.207e-5 http://gnomad.broadinstitute.org/variant/17-78086418-C-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Juvenile Late Onset Pompe Disease

Case85

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.784G>A (p.Glu262Lys)

ClinVar: 188806 https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: East Asian 5.016e-5, Overall 1.417e-5 http://gnomad.broadinstitute.org/variant/17-78081447-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 2 other patients have the same genotype

Case10

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1978C>T (p.Arg660Cys)

ClinVar: 558604 https://www.ncbi.nlm.nih.gov/clinvar/variation/558604/

gnomAD: East Asian 5.554e-5, Overall 4.142e-6 http://gnomad.broadinstitute.org/variant/17-78086764-C-T

Variant2: NM_000152.4:c.2221G>A (p.Asp741Asn)

ClinVar: 571521 https://www.ncbi.nlm.nih.gov/clinvar/variation/571521/

gnomAD: East Asian 1.087e-4, Overall 7.971e-6 http://gnomad.broadinstitute.org/variant/17-78090798-G-A

CaseAddInfo: Infantile Onset Pompe Disease

Case27

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1411_1414delGAGA (p.Glu471fs*5)

ClinVar: 188874 https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: East Asian 2.513e-4, Overall 1.781e-5 http://gnomad.broadinstitute.org/variant/17-78083827-CGAGA-C

Significance of this variant is unknown.

Variant2: NM_000152.4:c.460_465del (Arg154_Thre155del)

ClinVar: 551306 https://www.ncbi.nlm.nih.gov/clinvar/variation/551306/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case58

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1143delC (p.Ala382Leufs*10)

CAID: 370263 https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/

gnomAD: European (Non-Finnish) 8.946e-6, Overall 4.031e-6 http://gnomad.broadinstitute.org/variant/17-78082353-AC-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case32

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.1933G>A (p.Asp645Asn)

ClinVar: 188728 https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/

gnomAD: African 6.599e-5, Overall 8.250e-6 http://gnomad.broadinstitute.org/variant/17-78086719-G-A

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant, 1 more patient has the same genotype

Case21

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.1129G>C (p.Gly377Arg)

ClinVar: 497033 https://www.ncbi.nlm.nih.gov/clinvar/variation/497033/

gnomAD: European (Non-Finnish) 2.356e-5, Overall 1.072e-5 http://gnomad.broadinstitute.org/variant/17-78082341-G-C

CaseAddInfo: Infantile Onset Pompe Disease

Case4HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.1 pmol/punch/hr, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C

CaseAddInfo:

Case17HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.38 umol/g/h, GAA activity at 12.7% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2242dupG (p.Glu748Glyfs)

ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/

gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG

CaseAddInfo:

Case8HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 8 pmol/punch/hr, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2242dupG (p.Glu748Glyfs)

ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/

gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG

CaseAddInfo:

Case2HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 6 pmol/punch/hr, GAA activity at 25% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

Case14HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.1 umol/h/L, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C

CaseAddInfo:

Patient7: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1432G>A (p.Gly478Arg)

ClinVar: 551295, https://www.ncbi.nlm.nih.gov/clinvar/variation/551295/

gnomAD: 8.525e-06, http://exac.broadinstitute.org/variant/17-78083849-G-A

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: n/a

Patient4: Female, southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.2185delC (p.Leu729Trpfs) **this is not the same protein transcript listed in paper (p.Thr729fsX8) but I could not find this in clinvar or allele registry)

ClinVar: 370552, https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/

gnomAD: n/a

Case31: Female, 15 yr diagnosis, 15.9 yr report

HPOsFreeText: FVC z-score sitting 1.33 (116% pred), FVC z-score supine 1.2 (115% pred), 100% MRC Scale, 1040 CK U/l, 2.5 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case6: Male, 1 yr onset, 2 yr diagnosis, 8.2 yr report

CasePresentingHPOs: HP:0001371 (Contractures)

HPOsFreeText: Wheelchair partially used, FVC z-score sitting -3.47 (59% pred), FVC z-score supine -4.36 (48% pred), 79% MRC Scale, 3078 CK U/l, 4.5 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No respiratory support

Case14: Male, 7 yr onset, 10 yr diagnosis, 10.7 yr report

CasePresentingHPOs: HP:0002650 (Scoliosis)

HPOsFreeText: Wheelchair used, Respiratory support at night, FVC z-score sitting -2.22 (75% pred), 80% MRC Scale, 540 CK U/l, 8,9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

Case17: Male, 13 yr onset, 14 yr diagnosis, 14.3 yr report

HPOsFreeText: FVC z-score sitting -1.68 (81% pred), FVC z-score supine -1.77 (80% pred), 95% MRC Scale, 2935 CK U/l, 6.2 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case10: Male, 2.5 yr onset, 3 yr diagnosis, 13 yr report

CasePresentingHPOs: HP:0001371 (Contractures)

HPOsFreeText: FVC z-score sitting -3.01 (66% pred), FVC z-score supine -4.09 (54% pred), 84% MRC Scale, 1960 CK U/l, 8.6 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case23: Female, 1 yr onset, 1.9 yr diagnosis, 12.5 yr report

CasePresentingHPOs: HP:0002650 (Scoliosis)

HPOsFreeText: Wheelchair used at 6 yr, Respiratory support used at 6 yr, 10% MRC Scale, 1381 CK U/l, Deficient GAA activity (nmol/h/mg)^h from cultured fibroblasts

CaseLP2-6: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.10 umol/hr/L, Serum CK at 103 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1004G>A (p.Gly335Glu)

ClinVar: 180142 https://www.ncbi.nlm.nih.gov/clinvar/variation/180142/

gnomAD: Not in gnomAD

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

CaseOPOPD-64: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.72 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseOPOPD-43: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.20 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1082C>T (p.Pro361Leu)

ClinVar: 403712 https://www.ncbi.nlm.nih.gov/clinvar/variation/403712/

gnomAD: Latino 5.798e-5, Overall 1.203e-5 http://gnomad.broadinstitute.org/variant/17-78082294-C-T

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-78: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.91 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2214G>A (p.Trp738Ter)

ClinVar: 370223 https://www.ncbi.nlm.nih.gov/clinvar/variation/370223/

gnomAD: East Asian 5.437e-5, Overall 3.986e-6 http://gnomad.broadinstitute.org/variant/17-78090791-G-A

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy

CaseOPOPD-61: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.63 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseOPOPD-63: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.05 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseOPOPD-72: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.31 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2662G>T (p.Glu888Ter)

ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 2 other patients have the same genotype

CaseOPOPD-38: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.56 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.784G>A (p.Glu262Lys)

ClinVar: 188806 https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: East Asian 5.016e-5, Overall 1.417e-5 http://gnomad.broadinstitute.org/variant/17-78081447-G-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.47 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.546+5G>T

ClinVar: 557811 https://www.ncbi.nlm.nih.gov/clinvar/variation/557811/

gnomAD: East Asian 4.978e-4, Overall 3.824e-5 http://gnomad.broadinstitute.org/variant/17-78078936-G-T

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with only one copy, 2 other patients have the same genotype

CaseIP2-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.08 umol/hr/L, Serum CK at 385 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1194+2T>C

ClinVar: 370077 https://www.ncbi.nlm.nih.gov/clinvar/variation/370077/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant3: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 1 and 2 are in trans, also that Variant 3 is in cis with only one of them

CaseLP2-10: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.06 umol/hr/L, Serum CK at 670 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.2662G>T (p.Glu888Ter)

ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T

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

CaseOPOPD-62: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.85 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

Case13: 56yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0004887, HP:0020038

HPOsFreeText: GAA = 6.3%, BMI = 22.5, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 24yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

CaseLOPD-17: 6 weeks diagnosis

HPOsFreeText: GAA activity 6.5 (nmol · h−1 · mg−1), Mean percentage of normal 9.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1552-3C>G

ClinVar: 419722 https://www.ncbi.nlm.nih.gov/clinvar/variation/419722/

gnomAD: European (Non-Finnish) 2.713e-4, Overall 1.344e-4 http://gnomad.broadinstitute.org/variant/17-78084737-C-G

CaseAddInfo: Late Onset Pompe Disease

CasePD/Pathogenic-2: 3 weeks diagnosis

HPOsFreeText: GAA activity 8.8 (nmol · h−1 · mg−1), Mean percentage of normal 12.4%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2646+2T>A

ClinVar: 188924 https://www.ncbi.nlm.nih.gov/clinvar/variation/188924/

gnomAD: Not in gnomAD

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-19: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.8%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1115A>T (p.His372Leu)

ClinVar: 370483 https://www.ncbi.nlm.nih.gov/clinvar/variation/370483/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

CasePD/VOUS-3: 2 weeks diagnosis

HPOsFreeText: GAA activity 11.3 (nmol · h−1 · mg−1), Mean percentage of normal 15.8%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.664G>A (p.Val222Met)

ClinVar: 290223 https://www.ncbi.nlm.nih.gov/clinvar/variation/290223/

gnomAD: South Asian 5.393e-3, Overall 6.931e-4 http://gnomad.broadinstitute.org/variant/17-78079665-G-A

CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-18: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.0%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2188G>T (p.Glu730Ter)

ClinVar: 495665 https://www.ncbi.nlm.nih.gov/clinvar/variation/495665/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

CasePD/VOUS-2: 2 weeks diagnosis

HPOsFreeText: GAA activity 16.6 (nmol · h−1 · mg−1), Mean percentage of normal 23.3%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2069C>T (p.Pro690Leu)

ClinVar: 424308 https://www.ncbi.nlm.nih.gov/clinvar/variation/424308/

gnomAD: East Asian 1.077e-4, Overall 2.337e-5 http://gnomad.broadinstitute.org/variant/17-78087045-C-T

CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-14: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2509C>T (p.Arg837Cys)

ClinVar: 456408 https://www.ncbi.nlm.nih.gov/clinvar/variation/456408/

gnomAD: European (Non-Finnish) 4.676e-5, Overall 2.487e-5 http://gnomad.broadinstitute.org/variant/17-78092019-C-T

CaseAddInfo: Late Onset Pompe Disease

Patient8: Female

CasePresentingHPOs: HP:0004887, HP:0002194

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, able to sit independently, reversal of HCM, CRIM positive

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Symptom onset, diagnosis, and ERT at 4mo, ERT last for 54mo, ventilation required at 60 mo, died at 60mo

CasePMIDs: 14695532, 14972326

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

Patient10: Male

CasePresentingHPOs: HP:0002194, HP:0001522

HPOsFreeText: ERT dosage = 40 mg/kg/w, HCM reversal, CRIM positive

CaseNotHPOs: HP:0004887

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 3w, diagnosis at 3mo, ERT at 5mo, ERT lasted for 5mo, died at 12mo

CasePMIDs: 22644586, 14695532

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)

ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A

Patient17: Female

CasePresentingHPOs: HP:0004887, HP:0003819

HPOsFreeText: ERT dosage = 20mg/kg/2w, able to sit, CRIM positive

CaseNotHPOs:

NotHPOsFreeText: no HCM reversal

CaseAddInfo: Symptom onset at 3mo, diagnosis at 6mo, ERT at 10mo, ERT lasted for 6mo, required ventilation at 26mo, died at 28mo

CasePMIDs: 22644586, 14695532

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)

ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A

Patient5: Female

CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis and ERT at 4mo, ERT lasted for 1mo, ventilation required at 3mo, died at 5mo, variants in trans

CasePMIDs: 21763167, 11738358

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/17-78086424-C-T

Patient13: Female

CasePresentingHPOs:

HPOsFreeText: ERT dosage = 20mg/kg/2w, HCM reversal, CRIM positive, able to run and climb stairs, can speak well

CaseNotHPOs: HP:0004887, HP:0009046

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 111mo, currently 10yo

CasePMIDs: 14695532, 14972326

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

Patient 12: male

CasePresentingHPOs:

HPOsFreeText: CRIM positive, infusion associated reaction, heart normalization

CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0002546, HP:0000365, HP:0001371

CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 3yo, ERT at 4yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

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

gnomAD: 1.663e-05, http://exac.broadinstitute.org/variant/17-78085800-T-C

Patient8: Female

CasePresentingHPOs: HP:0004887, HP:0001270

HPOsFreeText: CRIM positive, tracheostomy partial heart normalization

CaseNotHPOs: HP:0025156, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 1yo, diagnosis at 9yo, ERT at 10yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4(GAA):c.670C>T (p.Arg224Trp)

ClinVar: 189188, https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/

gnomAD: 2.53e-05, http://exac.broadinstitute.org/variant/17-78079671-C-T

Patient18: Male

CasePresentingHPOs: HP:0004887, HP:0001270, HP:0002546

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, heart normalization

CaseNotHPOs: HP:0025156, HP:0000365, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: homozygous variants in trans, symptom onset at 1yo, diagnosis at 1.5yo, ERT at 4yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Patient5: female

CasePresentingHPOs: HP:0001270

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:25.600, infusion associated reaction, heat normalization

CaseNotHPOs: HP:0004887, HP:0025156, HP:0001371

CaseAddInfo: homozygous variants in trans, symptom onset and diagnosis at 1yo, ERT at 2yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Patient13: female

CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365

HPOsFreeText: CRIM positive, tracheostomy, partial heart normalization

CaseNotHPOs: HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 6yo, diagnosis and ERT at 11yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)

ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

gnomAD: 5.884e-05, http://exac.broadinstitute.org/variant/17-78086713-G-A

Family 3 - Patient 3

FamilyPresentingHPOs: HP:0002355, HP:0003701, HP:0000467, HP:0003327, HP:0002111, HP:0040081, HP:0100284

HPOsFreeText: Vacuolar myopathy, myopathic muscle unit action potentials

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003691, HP:0003306, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: female, 2yo at onset, 26yo at diagnosis, MRC sum score = 76, NIV used beginning at 22yo

FamilyPreviousTesting: Respiratory Evaluation: FVC = 31%, CK = 1,551 U/L, Vacuolar myopathy present in muscle pathology exam, DBS enzyme activity (with inhibition) = 5.1 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.1004G>A (p.Gly335Glu)

ClinVar: 180142, https://www.ncbi.nlm.nih.gov/clinvar/variation/180142/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Family 9 - Patient 9

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0010628, HP:0003306, HP:0002111, HP:0040081

HPOsFreeText: muscle pathology with slight vacuolar myopathy with mild glycogen excess

FamilyNotHPOs: HP:0002015, HP:0003691, HP:0002650

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: onset at 28yo, diagnosed at 35yo, MRC sum score = 81

FamilyPreviousTesting: Respiratory Evaluation: FVC = 71%, CK = 748 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 3.5 μmol/L/h

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.1799G>A (p.Arg600His)

ClinVar: 370130, https://www.ncbi.nlm.nih.gov/clinvar/variation/370130/

gnomAD: 8.675e-06, http://exac.broadinstitute.org/variant/17-78086421-G-A

Patient22: Male, 30 years report, 23 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 1.1% from leukocyte, Wheelchair needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient28: Male, 70 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.7% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient16: Female, 36 years report, 28 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 1% from a dried blood spot

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient32: Female, 19 years onset

CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098, HP:0002240, HP:0002910 (Cardiomegaly, Muscle weakness, Respiratory distress, Hepatomegaly, Abnormal liver function)

HPOsFreeText: Wheelchair needed, Respiratory Assistance needed

CaseAddInfo: LOPD

Patient10: Male, 39 years report, 17 years onset

CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098, HP:0002240 (Cardiomegaly, Muscle weakness, Respiratory distress, Hepatomegaly)

HPOsFreeText: GAA activity 9.3% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseAddInfo: LOPD

Patient8: Female, 61yo

CasePresentingHPOs: HP:0000822, HP:0003077

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 21yr disease duration, ERT lasted for 63mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1478C>T (p.Pro493Leu)

ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/

gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T

Patient5: Male, 52yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 15yr disease duration, ERT lasted for 63mo, 5yr follow-up MRI

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1478C>T (p.Pro493Leu)

ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/

gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T

Patient17: Male, 81yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 6yr disease duration, ERT lasted 37mo

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.925G>A (p.Gly309Arg)

ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Patient9: Male, 64yo

CasePresentingHPOs: HP:0000822, HP:0000819, HP:0001513

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 11yr disease duration, ERT lasted 14mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.925G>A (p.Gly309Arg)

ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Patient10: Female, 75yo

CasePresentingHPOs: HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 40yr disease duration, ERT lasted 103mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NC_000017.11:g.(?80118193)(80118357_?)del (del exon 18)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Patient6: Male, 36yo at diagnosis, 40yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 1.2 (2-10)

CaseNotHPOs:

NotHPOsFreeText: NIV and mobility aid not used

CaseAddInfo: 11yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)

ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/

gnomAD: n/a

Patient15: Female, 48yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.48 (3-20), NIV required only after ERT

CaseNotHPOs:

NotHPOsFreeText: mobility aid not required

CaseAddInfo: 33yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)

ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/

gnomAD: n/a

Patient21: Male, 56yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.57 (2-10), NIV and mobility aid required before and after ERT, developed wheelchair dependence after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 35yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs)

ClinVar: 189041, https://www.ncbi.nlm.nih.gov/clinvar/variation/189041/

gnomAD: n/a

Patient22: Female, 40yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:12,800, enzyme = 2.77 pmol/punch/h (7.3–39), NIV and mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 18yr disease duration, patient discontinued ERT, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.258dupC (p.Asn87Glnfs)

ClinVar: 282842, https://www.ncbi.nlm.nih.gov/clinvar/variation/282842/

gnomAD: 2.653e-05, http://exac.broadinstitute.org/variant/17-78078636-T-TC

Patient 4: Male, 37yo at diagnosis, 41yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 2.1 (3-20), mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: NIV not used

CaseAddInfo: 10yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)

ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/

gnomAD: n/a

Patient17: Male, 34yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:800, enzyme (μmol/g/h) = 0.75 (3-20), NIV required only after ERT began

CaseNotHPOs:

NotHPOsFreeText: mobility aid not required

CaseAddInfo: 17yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_001079803.2(GAA):c.896T>C (p.Leu299Pro)

ClinVar: 180144, https://www.ncbi.nlm.nih.gov/clinvar/variation/180144/

gnomAD: n/a

Patient13: male, 32yo, juvenile onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 24.9 / 25 / n-a, WGMS = 3 / 3 / n-a

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481+102_2646+31del)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Case#: 3, age 48, age 41 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 3, no further information

CasePresenting HPOs:HP:0012378, HP:0003546, HP:0001324 (fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 63.85 NaG/AaGIA, 91% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.-32-3C>A

ClinVar: 371622

Variant 2:NM_000152.5(GAA):c.-32-3C>A

ClinVar: 371622

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 4, age 24, age 18 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 4, no further information

CasePresenting HPOs:HP:0012378, HP:0003546, HP:0001324 (fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: vacuolar myopathy biopsy PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 40.54 NaG/AaGIA, 90.54% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.2608C>T (p.Arg870Ter)

ClinVar: 189009

Variant 2: not reported

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 2/a, age 20, age 14 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 2, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 64.47 NaG/AaGIA, 92.28% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

ClinVar: 932904

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

ClinVar: 279811

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: Patient 11, male

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 24yo at onset, 47yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

CaseB: 40 years onset

CaseAddInfo: Late-Onset Pompe Disease

Case17: Male, 11 years onset, 15 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case15: Female, 39 years onset, 40 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 41, GAA Activity at ~6.5 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case18: Female, Unknown years onset, Unknown years diagnosis, 25 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case11: Male, 24 years onset, 58 years diagnosis, 62 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Scapula alata)

CaseAddInfo: Late-Onset Pompe Disease

CaseP1-GAA: Male, ethnicity = North African, country origin = Morocco

CasePresentingHPOs: HP:0010899, HP:0010916, HP:0003236

HPOsFreeText: enzyme activity = 0.61, CPK = 448 U/L, ALT = 48 U/L, AST = 98 U/L, CRIM positive

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: heterozygote, variants in trans. Patient underwent ERT.

CasePreviousTesting: initial and confirmatory DBS, biochemical tests, echocardiography

CaseGenotypingMethod: mutation analyses

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

CaseVI,3: Adult onset, 64 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003236 (Proximal muscle weakness, Abnormal respiration, Increased serum CK)

HPOsFreeText: GAA activity from dried blood spot: 0.16%, Forced Vital Capacity Seated: 1550 (48%), Plasma CK 2.5-5x Normal

CaseAddInfo: Late-Onset Pompe Disease

Patient1: Female, Caucasian, 10yo

CasePresentingHPOs:

HPOsFreeText: IOPD, rhGAA IgG antibody titer = 400, CRIM positive

CaseNotHPOs:

NotHPOsFreeText: no infusion associated reactions

CaseAddInfo: homozygous, 6.5mo at diagnosis, 7.0mo at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)

ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: 0.00001809, https://gnomad.broadinstitute.org/variant/17-78079656-G-A

Case#: Patient 9, Gender N/A, Onset at 3-4 months. Death around 1-2 years, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001252, HP:0001270, HP:0001640, HP:0005165

Muscular hypotonia, Motor delay, Cardiomegaly, Shortened PR interval)

CaseHPOFreeText: BVH, Ejection fraction 10%, Creatine kinase levels 1,010u/l

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: No GAA measurement . Ejection fraction 10%, Creatine kinase levels 1,010u/l

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

Variant: NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

ClinVar: 550327

CAID: N/A

gnomAD: Highes population MAF = 0.0001427 (Others)

ParentalGenotype: Both parents were carriers for the viariant c.1941C>G (p.Cys647Trp)

PreviouslyPublished: N/A

Patient5:

CasePresentingHPOs:

HPOsFreeText: Juvenile onset Pompe

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 0.000007972, https://gnomad.broadinstitute.org/variant/17-78082197-T-C

Patient 15 - IOPD - homozygous

Variant: NM_000152.4(GAA):c.925G>A (p.Gly309Arg)

ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A

PatientF3P2: Female, 36 years diagnosis, European and Native American

CasePresentingHPOs: HP:0003236, HP:0012378, HP:0003547, HP:0009113, HP:0002910 (Increased serum CK, Fatigue, Shoulder weakness, Weak diaphragm, Increased transaminases)

HPOsFreeText: Decline in energy and strength reported with each of her four pregnancies most prominent after her youngest daughter's diagnosis of IOPD, Subsequent enzyme assay indicated deficient GAA activity via a dried blood spot (2.2 pmol/punch/hr, control >3.88 pmol/punch/hr), Pulmonary functioning tests (PFTs) showed a decrease in forced vital capacity (FVC) from 93% predicted seated to 72% predicted supine, Laboratory results demonstrated an elevated CK level of 490 U/L (control 30–220 U/L) and mild elevation of transaminases with AST of 83 U/L (control 15–41 U/L) and ALT of 60 U/L (control 14–54 U/L)

CaseAddInfo: Mother of proband F3P1, found to have minimally symptomatic LOPD

Case#: Downes_2019_BSS, male, age unknown, South-Asian ancestry reported

DiseaseAssertion: BSS

FamilyInfo: NR

ParentalGenotype: NR

CasePresentingHPOs: NR

PlateletAggregation: NR

CaseHPOFreeText: NR

CaseNotHPOs:

CaseNotHPOFreeText:

ProteinExpression: NR

CasePreviousTesting:

GenotypingMethod: HTS panel described in supplementary table 3

PreviouslyPublished:

Gene: ITGA2B

Variant: homozygous c.1005_1013del (p.His335_Leu338delinsGln)

HGVS: NM_000419.5(ITGA2B):c.1005_1013del

ClinVarID: 626948

CAID:

gnomAD: not found in v.2.1.1

MultipleGeneVariants:

Case: Charif Patient #60, 7yo at report, 6yo at dx, male, European

CasePresentingHPOs:

CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.25, OS:0.08; central scotoma; ODS: temporal atrophy

CaseNOTHPOs:

CaseNOTHPOSFreeText: other symptoms

CasePreviousTesting:

CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing

Variant: NM_001098.2 c.525+1G>A; c.220C>G p.(Leu74Val) compound heterozygous

ClinVarID: or CAID: 1470169

AddCaseInfo: no segregation data

PreviouslyPublished: n/a

VariantEvidence: n/a

Case: Charif Patient #1, 25yo at report, female, European

CasePresentingHPOs:

CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.5, OS:0.63; ODS: diffuse loss;

CaseNOTHPOs:

CaseNOTHPOSFreeText: other symptoms

CasePreviousTesting:

CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing

Variant: NM_001098.2 c.172C>T p.(Arg58*) heterozygous

ClinVarID: or CAID: 441075

AddCaseInfo: no segregation data

PreviouslyPublished: n/a

VariantEvidence: n/a

Case#: KMP 15, female, 82 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: yes

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 60%; NYHA III.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2734A>G (p.Lys912Glu)

ClinVar: 520267 https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/

CAID: n/a

gnomAD: absent

Variant not found in the supplemental data even though Mastermind says it is in S002.

Variant not found in the supplemental data even though Mastermind says it is in S002.

Case#: Consequence 7 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1608G>T (p.Glu536Asp)

ClinVar: 177671 https://www.ncbi.nlm.nih.gov/clinvar/variation/177671/

CAID: n/a

gnomAD: absent

Case#: Consequence 5 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2198G>T (p.Gly733Val)

ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/

CAID: n/a

gnomAD: absent

Case#: Consequence 8 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)

ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

CAID: n/a

gnomAD: absent

This variant is mentioned only in reference to a previous publication (PMID: 30689204)

Ser112Arg is mentioned in this table in reference to previous publications

Case#: Patient #17, Brazilian

DiseaseAssertion: MPS1, mild

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: survival beyond age 35

CaseNotHPOs:

CaseNotHPOFreeText: mental retardation

GenotypingMethod:

PreviouslyPublished:

Variant: Q380R; R628P (also A8, A20, L14)

ClinVar: 1064675

CAID:

SupplementalData:

Another family has this variant in homozygosity, but they are also of Arab origin and are said to be from the same village, so conservatively not scoring for PM3 since this is a founder variant. Could add to segregation data, but PP1 is already at the maximum weight

Previously published cases from PMID: 22405087

Patient 2 in the supplemental info has the same genotype, phenotype, and gender as from PMID: 30689204, so it seems likely that this is the same individual.

Case4: Male, 45 years report, 44 years diagnosis, Germany

CasePresentingHPOs:

HPOsFreeText: 6-min walk test at 510 (m)

CaseNotHPOs: HP:0002878 (Respiratory failure)

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 0 years on ERT

Case3: Male, 27 years report, 20 years diagnosis, Germany

CasePresentingHPOs: HP:0002878 (Respiratory failure)

HPOsFreeText: 6-min walk test at 201 (m)

CaseNotHPOs:

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 7 years on ERT

This variant is mentioned only in reference to a previous publication (PMID: 34056600)

This variant is mentioned only in reference to previous publications (PMID: 22405087, 26992325, 28463998)

Previously published in PMID 30689204

This variant is mentioned only in reference to a previous report.

This variant is only mentioned in reference to a previous report.

Case#: Spiegel Patient V-2 (proband not designated, so was chosen), female, 7yo at report, Arab Muslin origin

DiseaseAssertion: Infantile Cerebellar-Retinal Degeneration

FamilyInfo: All eight individuals were homozygous for the mutation; ten parents and one of the healthy sibs were heterozygous, and three healthy sibs were homozygous for the normal allele. 3 additional affected individuals are deceased, so it is possible that they were not genotyped and that may be the reason for the discrepancy in the count.

CasePresentingHPOs: HP:0000648, HP:0000639, HP:0012736, HP:0001252, HP:0001251, HP:0002194, HP:0100543, HP:0007359, HP:0002197, HP:0000556, HP:0002120, HP:0001272, HP:0033725, HP:0002500, HP:0001284, HP:0000407

CaseHPOFreeText: birth weight= 2,700 g (10th centile); birth head circumference= 35 cm (50th centile); initial manifestations: hypotonia and ataxia at 2 months; current weight= 11 kg (−5 SD); current head circumference= 46.5 cm (−3.5 SD); current motor skills= does not roll; current cognitive skills= smile, recognize family; focal and generalized seizures; severe retinal dystrophy dx at 1yo; mild cortical atrophy on MR scan at 3mo; severe cerebellar atrophy, moderate cortical atrophy (frontal and temporal), thin corpus callosum, abnormal white matter signal last MR scan at 4 yo; moderate sensorineural hearing loss

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: homozygosity mapping, WES

PreviouslyPublished: n/a

Variant: c.336C>G in ACO2 [MIM 100850] (NM_001098.2), which causes p.Ser112Arg (NP_001089.1). homozygous

ClinVar: 29584

FunctionalEvidence: Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded,

AdditionalInfo: 2 "unrelated" families reported, but "Affected individuals of both unrelated clans shared a similar homozygous haplotype, indicating that Ser112Arg is a founder mutation in this population" so will count the segregations as one family

SupplementalData: n/a