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

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.4075C>T (p.Arg1359Cys)

ClinVar: 178082, https://www.ncbi.nlm.nih.gov/clinvar/variation/178082/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23887513-G-A

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.4125T>A (p.Tyr1375Ter)

ClinVar: 579879, https://www.ncbi.nlm.nih.gov/clinvar/variation/579879/

gnomAD: n/a

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.5534G>A (p.Arg1845Gln)

ClinVar: 181286, https://www.ncbi.nlm.nih.gov/clinvar/variation/181286/

gnomAD: 0.000004023, https://gnomad.broadinstitute.org/variant/14-23884229-C-T

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

Case IV-8: Female, Iranian, 36yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0005162 (left ventricular dysfunction)

CaseHPOFreeText: New York Heart Association Class = I, left ventricular ejection fraction = 60%, left ventricular internal end-diastolic diameter = 5.0cm, left ventricular internal end-systolic diameter = 3.1cm, interventricular septum = 0.7cm, posterior wall = 0.7cm, normal sinus rhythm, Normal heart valve function

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG

CaseGenotypingMethod: co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

Case III-10: Female, Iranian, 60yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0011713, HP:0005162, HP:0005185, HP:0002375 (mitral regurgitation, left bundle branch block, left ventricular dysfunction, systolic dysfunction, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 15-20%, left ventricular internal end-diastolic diameter = 5.6cm, left ventricular internal end-systolic diameter = 4.3cm, interventricular septum = 0.7cm, posterior wall = 0.6cm, Normal heart valve function, grade II diastolic dysfunction

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG

CaseGenotypingMethod: co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Case IV-6: Female, Iranian, 34yo at diagnosis, 37yo at study

DiseaseAssertion: DCM (initially); paper notes that phenotype is more consisted with hypokinetic non-dilated cardiomyopathy based on guideline from ESC working group on myocardial and pericardial diseases (PMID: 26792875)

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0002375 (mitral regurgitation, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 35%, left ventricular internal end-diastolic diameter = 5.2cm, left ventricular internal end-systolic diameter = 4.2cm, interventricular septum = 0.9cm, posterior wall = 1.0cm, normal sinus rhythm, grade I diastolic function

CaseNotHPOFreeText:

CasePreviousTesting: ECG, Full testing (https://hyp.is/2c24ajtuEemXQ-fRmGkjTA/www.sciencedirect.com/science/article/pii/S1769721217300484)

CaseGenotypingMethod: https://hyp.is/IKjfsDtxEem3Sh8RHHdYSg/www.sciencedirect.com/science/article/pii/S1769721217300484) WES, targeted exome sequence capture using SureSelectXT Human All Excon v5 kig (Agilent), co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Supplementary Data: Table 2

Case C: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, CSRP3, DES, LMNA, MYBPC3, TNNT2, TNNI3)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case E: proband, male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) PRDM16 Variant:

Variant: NM_022114.3(PRDM16):c.2666C>T (p.Pro889Leu)

ClinVar: 487607, https://www.ncbi.nlm.nih.gov/clinvar/variation/487607/

gnomAD: 0.0001771, https://gnomad.broadinstitute.org/variant/1-3331186-C-T

Supplementary Data: Table 2

Case G: proband, Male

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case I: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

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

Supplementary Data: S2 Table

Case 126: Spanish, 12yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: n/a

Supplementary Data: S2 Table

Case 49: Spanish, 18yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant1: NM_000257.3(MYH7):c.2890G>C (p.Val964Leu)

ClinVar: 42938, https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/

gnomAD: 0.0004383, https://gnomad.broadinstitute.org/variant/14-23893148-C-G

Variant2: NM_000257.3(MYH7):c.3613G>A (p.Glu1205Lys)

ClinVar: 179656, https://www.ncbi.nlm.nih.gov/clinvar/variation/179656/

gnomAD: 0.000004004, https://gnomad.broadinstitute.org/variant/14-23889167-C-T

Case#: male, 43 yrs,

DiseaseAssertion: FDCM

FamilyInfo: Family B; sister also proband; brother died of SCD; daughter and father asymptomatic

CasePresentingHPOs: HP:0012250 (ST segment depression)

CaseHPOFreeText: severe cardiac enlargement, increased LVEDD (77.8 mm), decreased LVESD (69.8 mm), decreased LVEF (21% < 50%), heart rate 78 beats/min, widened QRS complex (120 ms > 110 ms)

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: N/A

CaseGenotypingMethod: Sanger sequencing, Genome Analyzer IIx, ECG,

Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

Case#: female

DiseaseAssertion: FDCM

FamilyInfo: Family B; brother also proband; brother died of SCD, niece and father asymptomatic

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Sanger sequencing, Genome Analyzer IIx, ECG,

Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

CaseHCM014: 43 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy)

HPOsFreeText: Maximal LV thickness 27 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00004657, http://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseHCM133: 64 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 21 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3551A>T (p.Gln1184Leu)

ClinVar: 181226 https://www.ncbi.nlm.nih.gov/clinvar/variation/181226/

gnomAD: 0.0006115, http://gnomad.broadinstitute.org/variant/14-23889229-T-A

Multiple Gene Variants

(1) MYH6 Variant

Variant: NM_002471.3(MYH6):c.1252G>A (p.Val418Met)

ClinVar: 44449 https://www.ncbi.nlm.nih.gov/clinvar/variation/44449/

gnomAD: 0.001954, http://gnomad.broadinstitute.org/variant/14-23870076-C-T

CaseHCM083: 53 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0001667, HP:0001705 (Exertional dyspnea, Left ventricular hypertrophy, Right ventricular hypertrophy, Right ventricular outlet obstruction)

HPOsFreeText: Maximal LV thickness 18 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23887429-C-T

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

Supplementary Data: Table S3

Case 90:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.745C>T (p.Arg249Ter)

ClinVar: 407183, https://www.ncbi.nlm.nih.gov/clinvar/variation/407183/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23900678-G-A

MultipleGeneVariants:

(1) TPM1 Variant:

Variant: NM_001018004.1(TPM1):c.775A>G (p.Lys259Glu)

ClinVar: 43687, https://www.ncbi.nlm.nih.gov/clinvar/variation/43687/

gnomAD: 0.0008382, https://gnomad.broadinstitute.org/variant/15-63363291-A-G

(2) PRKAG2 Variant:

Variant: p.Lys133Ile no ClinVar or CAID

Supplementary Data: Table S3

Case 12:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.5786C>T (p.Thr1929Met)

ClinVar: 181397, https://www.ncbi.nlm.nih.gov/clinvar/variation/181397/

gnomAD: 0.00005308, https://gnomad.broadinstitute.org/variant/14-23882972-G-A

Case: Case 9, male, 69yo

CasePresentingHPOs: HP:0031318 (myocardial fiber disarray)

HPOsFreeText: BMI = 25.2kg/m^2, cause of death: accidental head injury, heart weight = 624g, left ventricular thickness = 1.8cm, distribution of myocyte disarray in ventricular septum, area of disarray = 7.8%, grade of fibrosis = 3

CaseNotHPOs: HP:0031296 (atrial septal hypertrophy)

CasePreviousTesting: NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

CaseGenotypingMethod: genomic DNA extracted from whole blood, PCR, NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

Variant: NM_000257.4(MYH7):c.2822G>A (p.Arg941His)

ClinVar: 636633, https://www.ncbi.nlm.nih.gov/clinvar/variation/636633/

gnomAD: 0.00001590, https://gnomad.broadinstitute.org/variant/14-23893216-C-T?dataset=gnomad_r2_1

Supplementary Data Table S3

Case: 52

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2451C>A (p.Asn817Lys)

ClinVar: 235029, https://www.ncbi.nlm.nih.gov/clinvar/variation/235029/

gnomAD: absent

MultipleGeneVariants:

(1) TTN Variant

Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)

ClinVar: 165840, https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/

gnomAD: absent

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

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

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

CaseVIII: Early adult onset, 56 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326, HP:0003198 (Proximal muscle weakness, Increased serum CK, Easy fatiguability, Myalgia, Myopathy)

HPOsFreeText: GAA activity from dried blood spot: 0.13%, Forced Vital Capacity Seated: 2480 (75%), Plasma CK 2.5-5x Normal, 6-Minute Walking Test: 385 min

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease, Reduced staining for dystrophin in patient VIII suggested Becker dystrophy before LOPD diagnosis

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

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

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

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

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

Patient26: Female

CasePresentingHPOs: HP:0004887, HP:0001270, HP:0001371

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

CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 3yo, diagnosis at 5yo, ERT at 8yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

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

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

Patient14: male

CasePresentingHPOs: HP:0004887, HP:0040288, HP:0002546, HP:0000365

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:204.800, immunomodulation, infusion associated reaction, able to sit independently, partial heart normalization

CaseNotHPOs: HP:0001371

CaseAddInfo: homozygous variants in trans. Symptom onset, diagnosis and ERT at 4yo.

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

Patient17: Male

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

HPOsFreeText: CRIM negative, tracheostomy, heart normalization

CaseNotHPOs: HP:0000365, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: homozygous variants in trans, symptom onset at 2yo, diagnosis and ERT at 6yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1A>G (p.Met1Val)

ClinVar: 188785, https://www.ncbi.nlm.nih.gov/clinvar/variation/188785/

gnomAD: n/a

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

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

Case23: Male, 77 years report

HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 120 meters, Forced Vital Capacity at 40%

GenotypingMethod: GAA Gene Sequencing

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

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

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

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

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

gnomAD: Ashkenazi Jewish 1.010e-4, Overall 2.860e-5 http://gnomad.broadinstitute.org/variant/17-78081665-G-A

CaseAddInfo: Late Onset Pompe Disease

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

Patient14: Female, 54yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 18yr disease duration, ERT lasted 44mo

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

Patient19: Female, 61yo

CasePresentingHPOs: HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2yr disease duration, ERT lasted 9mo

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

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

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

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

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

Patient 11 - LOPD

Variant1: NM_000152.4(GAA):c.670C>T (p.Arg224Trp)

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

gnomAD: 0.00002184, http://gnomad.broadinstitute.org/variant/17-78079671-C-T

Variant2: NM_000152.4(GAA):c.2331+2T>A

ClinVar: 371281, https://www.ncbi.nlm.nih.gov/clinvar/variation/371281/

gnomAD: 0.000004033, http://gnomad.broadinstitute.org/variant/17-78090910-T-A

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

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

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

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

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

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

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

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

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

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

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

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

Case28

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.1099T>C (p.Trp367Arg)

ClinVar: 555820 https://www.ncbi.nlm.nih.gov/clinvar/variation/555820/

gnomAD: Not in gnomAD

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

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

gnomAD: East Asian 6.418e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78086424-C-T

CaseAddInfo: Infantile Onset Pompe Disease

Case47

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.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

Variant2: NM_000152.4:c.1979G>A (p.Arg660His)

ClinVar: 189172 https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/

gnomAD: African 2.546e-4, Overall 3.680e-5 http://gnomad.broadinstitute.org/variant/17-78086765-G-A

CaseAddInfo: Infantile Onset Pompe Disease

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

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/

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

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 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

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

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

Case#: Patient 8, male

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 30yo at onset, 35yo at diagnosis

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

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

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

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

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

gnomAD: n/a

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

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

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

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

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

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

Case2: Female, 44 years onset, 54 years diagnosis, 65 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

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

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/

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

Case9: 0.4 years diagnosis, Germany

CasePresentingHPOs: HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

HPOsFreeText: 18 BNP (pg/ml), 2.42 IVS (d) z score, 1.82 IVS (s) z score, Heart Failure at NYHA Class 1

NotHPOsFreeText: No left-ventricular outflow tract obstruction

CaseAddInfo: Infantile-Onset Pompe Disease

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

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

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

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

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

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

Patient21: Male, 35 years report, 1y< years onset

CasePresentingHPOs: HP:0001324, HP:0002240 (Muscle weakness, Hepatomegaly)

CaseAddInfo: LOPD

Patient11: Male, 10 years report, 4 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 16.9% from leukocyte

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

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient38: Male, 20 years report, 2 year onset

CasePresentingHPOs: HP:0001324, HP:0002098, HP:0002527 (Muscle weakness, Respiratory distress, Falls)

HPOsFreeText: GAA activity 2.7% from leukocyte, Wheelchair needed, Respiratory Assistance needed

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

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

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

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)