CaseMYH7-5: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.2155C>T (p.Arg719Trp)

ClinVar: 14104 https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/

gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A

CaseMYH7-1: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.2803G>A (p.Glu935Lys)

ClinVar: 14106 https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: Not in gnomAD

Case2: female, 16 years old

DiseaseAssertion: Myopathy

FamilyInfo:

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0003722, HP:0001371, HP:0009027, HP:0012515

"Toe walking, Scoliosis, Neck flexor weakness, Flexion contractures, Foot dorsiflexor weakness, Hip flexor weakness"

CaseHPOFreeText: Presented with toe-walking at age 5 years and required bilateral tendo-Achilles releases at ages 7 and 13 years. A progressive scoliosis required surgical stabilization at age 12 years. At age 13 years neck movements were markedly restricted in all directions except extension, and there were mild flexion contractures at the hips, knees and ankles. There was marked neck flexion weakness, moderate weakness of hip extension and ankle dorsiflexion, and mild weakness of shoulder abduction, hip flexion and knee flexion/extension. While walking her upper body was angled forward, there was external rotation of the feet and mild foot-drop. The axial involvement in this case largely spares the lumbar musculature and is restricted to the upper thoracic and neck regions.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Serum creatine kinase was 308 iu/l (24–215). There was moderate restrictive lung disease (as determined by formal pulmonary function testing) at age 12 years (FVC 55% of predicted). Electromyography, sural nerve biopsy and cardiac investigations (EKG and echocardiogram) were normal. A quadriceps muscle biopsy taken at age 13 years demonstrated congenital fiber type disproportion. There was type 1 fiber predominance (82%), marked type 1 hypotrophy and type 2 fiber hypertrophy. Muscle MRI scan at age 12 years showed selective fatty infiltration of spinalis muscles in the upper thoracic and cervical regions. Unreported heterozygous variants in RYR1 (p.Asn4200Ser), COL6A3 (p.Ser2829Pro) and TTN (p.Gly4604Glu) were detected, but were all present in a healthy parent. In addition, Sanger sequencing was normal for ACTA1, SEPN1, LMNA, TPM3, TPM2, TNNT1 and MYOZ2.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was found by whole exome sequencing studies, and confirmed by Sanger sequencing. This change was absent in parental DNA samples.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

Case: Family A proband, female, Saudi Arabia, 10mo at presentation

CasePresentingHPOs: HP:0001635, HP:0001644, HP:0005185, HP:0012664, HP:0006677, HP:0011713 (heart failure, dilated cardiomyopathy, global systolic dysfunction, reduced ejection fraction, prolonged QRS complex, left bundle branch block)

HPOsFreeText: decompensated heart failure, diastolic dysfunction, left ventricle end-diastolic diameter = 120cm, left ventricular end systolic diameter = 0.4cm, left ventricular ejection fraction = 25%, left ventricular posterior wall thickness = 0.4cm, heat rate = 140bpm

CaseNotHPOs: HP:0011703 (sinus tachycardia)

FamilyInfo: consanguineous, family history of heart disease, pedigree in Fig. 1

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, TPM1, ACTC1; 181 genes, Supplementary Data Table S1

CaseGenotypingMethod: genomic DNA extracted from peripheral blood, NGS (181 genes, Supplementary Data Table S1), variants confirmed via Sanger sequencing, parents tested

InheritancePattern: autosomal dominant

Variant: NM_000257.3(MYH7):c.2770G>A (p.Glu924Lys)

ClinVar: 14092, https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/

gnomAD: n/a

MultipleGeneVariants:

(1) LAMA4 Variant

Variant: NM_001105206.2:c.3925G>A

CAID: CA365374078, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA365374078

gnomAD: n/a

Supplementary Data: Table S3

Case 7:

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.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

MultipleGeneVariants:

(1) TTN Variant:

Variant: p.Arg12731Ter no ClinVar or CAID

Supplementary Data: Table 2

Case L:

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

Supplementary Data: Table 2

Case N:

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, MYBPC3)

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 H: proband, Female

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 F: proband, Female

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, 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

Supplementary Data: Table 2

Case J: 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

Supplementary Data: Table 2

Case D: proband, female

DiseaseAssertion: Hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001639 (hypertrophic 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) DSC2 Variant:

Variant: NM_004949.4(DSC2):c.2194T>G (p.Leu732Val)

ClinVar: 36005, https://www.ncbi.nlm.nih.gov/clinvar/variation/36005/

gnomAD: 0.001181, https://gnomad.broadinstitute.org/variant/18-28650748-A-C

(2) DSG2 Variant:

Variant: NM_001943.4(DSG2):c.1174G>A (p.Val392Ile)

ClinVar: 36009, https://www.ncbi.nlm.nih.gov/clinvar/variation/36009/

gnomAD: 0.002137, https://gnomad.broadinstitute.org/variant/18-29111109-G-A

(3) DSP Variant:

Variant: NM_001008844.2(DSP):c.1778A>G (p.Asn593Ser)

ClinVar: 44867, https://www.ncbi.nlm.nih.gov/clinvar/variation/44867/

gnomAD: 0.0005695, https://gnomad.broadinstitute.org/variant/6-7571692-A-G

CaseMYH7-39: 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.952A>C (p.Thr318Pro)

CAID: CA389051682 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.952A%3EC

gnomAD: Not in gnomAD

CaseMYH7-26: 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A

CaseMYH7-22: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.2333A>T (p.Asp778Val)

ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/

gnomAD: Not in gnomAD

CaseMYH7-3: 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.5222_5223del (p.Val1741Glyfs*11)

CAID: CA913184899 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184899

gnomAD: Not in gnomAD

CaseMYH7-15: 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.2738T>C (p.Ile913Thr)

CAID: CA389047215 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2738T%3EC

gnomAD: Not in gnomAD

CaseMYH7-1: 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.5452C>T (p.Arg1818Trp)

ClinVar: 217826 https://www.ncbi.nlm.nih.gov/clinvar/variation/217826/

gnomAD: Latino 5.782e-5, Overall 7.956e-6 https://gnomad.broadinstitute.org/variant/14-23884311-G-A

Table 5

Case LO13: Italian

DiseaseAssertion: HCM (late-onset)

FamilyInfo: positive family history

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography

CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing

Variant: NM_000257.3(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Supplemental data table e-1

Case: MYH7 Case 1

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 29300372

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.1358G>A (p.Arg453His)

ClinVar: 42838, https://www.ncbi.nlm.nih.gov/clinvar/variation/42838/

gnomAD: n/a

Supplemental data table e-1

Case: MYH7 Case 2

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 27282841

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.5459G>A (p.Arg1820Gln)

ClinVar: 419278, https://www.ncbi.nlm.nih.gov/clinvar/variation/419278/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23884304-C-T

Supplementary Data Table S3

Case: 276

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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

MultipleGeneVariants:

(1) LAMA4 Variant

Variant: NM_001105206.3(LAMA4):c.3239G>A (p.Arg1080Gln)

ClinVar: 44374 https://www.ncbi.nlm.nih.gov/clinvar/variation/44374/

gnomAD: 0.02400, https://gnomad.broadinstitute.org/variant/6-112460365-C-T

(2) NEBL Variant

Variant: NM_006393.2(NEBL):c.109_110del (p.Leu37fs)

ClinVar: 229042 https://www.ncbi.nlm.nih.gov/clinvar/variation/229042/

gnomAD: 0.001673, https://gnomad.broadinstitute.org/variant/10-21185929-TAA-T

Supplementary Data Table S3

Case: 90

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.977G>A (p.Arg326Gln)

ClinVar: 42813 https://www.ncbi.nlm.nih.gov/clinvar/variation/42813/

gnomAD: 0.01364, https://gnomad.broadinstitute.org/variant/11-47367871-C-T

Supplementary Data Table S3

Case: 218

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.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.2686G>A (p.Val896Met)

ClinVar: 42652 https://www.ncbi.nlm.nih.gov/clinvar/variation/42652/

gnomAD: 0.02794, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

(2) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

(3) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

Supplementary Data Table S3

Case: 26

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) FBN1 Variant

Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)

ClinVar: 199948, https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/

gnomAD: 0.0006449, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

(2) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Data Table S3

Case: 245

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DES Variant

Variant: NM_001927.4(DES):c.638C>T (p.Ala213Val)

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(2) JUP Variant

Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)

ClinVar: 45842 https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/

gnomAD: 0.01341, https://gnomad.broadinstitute.org/variant/17-39913771-C-T

(3) TTN Variant

Variant: NM_001267550.2(TTN):c.33501_33503AGA[6] (p.Glu11172dup)

ClinVar: 46889 https://www.ncbi.nlm.nih.gov/clinvar/variation/46889/

gnomAD: 0.01788, https://gnomad.broadinstitute.org/variant/2-179544685-C-CTCT

Supplementary Data Table S3

Case: 25

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) GAL Variant

Variant: NM_015973.5(GAL):c.47C>T (p.Ala16Val)

ClinVar: 475915, https://www.ncbi.nlm.nih.gov/clinvar/variation/475915/

gnomAD: 0.006938, https://gnomad.broadinstitute.org/variant/11-68452438-C-T

Supplementary Data Table S3

Case: 47

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DOLK Variant

Variant: NM_014908.3(DOLK):c.1dup (p.Met1fs)

ClinVar: 167006, https://www.ncbi.nlm.nih.gov/clinvar/variation/167006/

gnomAD: 0.006541, https://gnomad.broadinstitute.org/variant/9-131709581-A-AT

Supplementary Data Table S3

Case: 373

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_000257.3:c.4903A>G (p.Met1635Val)

CAID: CA044177 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA044177

gnomAD: 0.0005972, https://gnomad.broadinstitute.org/variant/14-23885263-T-C

MultipleGeneVariants:

(1) LMNA Variant

Variant: NM_170707.4(LMNA):c.357C>T (p.Arg119=)

ClinVar: 48062 https://www.ncbi.nlm.nih.gov/clinvar/variation/48062/

gnomAD: 0.01294, https://gnomad.broadinstitute.org/variant/1-156100408-C-T

(2) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3181C>T (p.Gln1061Ter)

ClinVar: 42690 https://www.ncbi.nlm.nih.gov/clinvar/variation/42690/

gnomAD: 0.0001913, https://gnomad.broadinstitute.org/variant/11-47355117-G-A

(3) SCN5A Variant

Variant: NM_000335.4(SCN5A):c.553G>A (p.Ala185Thr)

ClinVar: 67996 https://www.ncbi.nlm.nih.gov/clinvar/variation/67996/

gnomAD: 0.004251, https://gnomad.broadinstitute.org/variant/3-38662392-C-T

(4) VCL Variant

Variant: NM_014000.2(VCL):c.1535G>A (p.Arg512His)

ClinVar: 450167 https://www.ncbi.nlm.nih.gov/clinvar/variation/450167/

gnomAD: 0.0001973, https://gnomad.broadinstitute.org/variant/10-75854211-G-A

Supplementary Data Table S3

Case: 111

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.1193G>A (p.Gly398Glu)

ClinVar: 180434 https://www.ncbi.nlm.nih.gov/clinvar/variation/180434/

gnomAD: 0.0001946, https://gnomad.broadinstitute.org/variant/14-23898502-C-T

MultipleGeneVariants:

(1) DSP Variant

Variant: NM_004415.4(DSP):c.5498A>T (p.Glu1833Val)

ClinVar: 44929 https://www.ncbi.nlm.nih.gov/clinvar/variation/44929/

gnomAD: 0.02491, https://gnomad.broadinstitute.org/variant/6-7582993-A-T

(2) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

(3) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

Supplementary Data Table S3

Case: 123

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DES Variant

Variant: NM_001927.4(DES):c.638C>T (p.Ala213Val)

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.02090, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Data Table S3

Case: 278

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.2348G>A (p.Arg783His)

ClinVar: 180437 https://www.ncbi.nlm.nih.gov/clinvar/variation/180437/

gnomAD: 0.00004005, https://gnomad.broadinstitute.org/variant/14-23894566-C-T

MultipleGeneVariants:

(1) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Material 4

Case M-23: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2546T>C (p.Met849Thr)

ClinVar: 42914, https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/

gnomAD: n/a

Supplementary Material 4

Case M-30: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2803G>A (p.Glu935Lys)

ClinVar: 14106, https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: n/a

Supplementary Material 4

Case M-9: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)

ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

gnomAD: n/a

Supplementary Material 4

Case M-26: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2609G>A (p.Arg870His)

ClinVar: 14120, https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

gnomAD: 0.000007072, https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Supplementary Data: Online Table 2b

Case 5:

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 1: 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

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607, https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

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:c.3100-2A>C

CAID: CA035633, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA035633

gnomAD: 0.00002475, https://gnomad.broadinstitute.org/variant/14-23891536-T-G

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:c.1915A>G

CAID: CA389049545, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049545

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.2704G>A (p.Glu902Lys)

ClinVar: 228905, https://www.ncbi.nlm.nih.gov/clinvar/variation/228905/

gnomAD: n/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.2678C>T (p.Ala893Val)

ClinVar: 177763, https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/

gnomAD: n/a

Supplementary Data: Online Table 1a

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.1106G>A (p.Arg369Gln)

ClinVar: 42822, https://www.ncbi.nlm.nih.gov/clinvar/variation/42822/

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:c.3928C>G

CAID: CA389041570, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041570

gnomAD: n/a

Case#: HCM431, male, 24 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 18mm LVST, 49mm LVEDD, 80% LVEF, 21mm Maxi LVWT, 80mmHg Maxi LVOTG, 95467544 raw RNA-seq reads, 91611504 HQ reads (95.96%), 96.60% mapping rate, 701266 total variant, 33263 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

CAID: N/A

gnomAD: absent

Case#: HCM483, male, 37 years, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 23mm LVST, 40mm LVEDD, 72% LVEF, 26mm Maxi LVWT, 70mmHg Maxi LVOTG, 132375212 raw RNA-seq reads, 125845538 HQ reads (95.07%), 96.52% mapping rate, 838862 total variant, 35806 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

CAID: N/A

gnomAD: 0.00001548 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case#: 16, female, diagnosed as fetus,

DiseaseAssertion: LVNC

FamilyInfo: yes

CasePresentingHPOs: cyanosis, Ebstein anomaly of the tricuspid valve, Ventricular septal defect, coarctation of aorta, congestive heart failure (HP:0000961, HP:0010316, HP:0001629, HP:0001680, HP:0001635)

CaseHPOFreeText: -5.47 Fathmm, 0 sift, 0.001 polyphen2, 0 GVGD, mutation taster 1, -3.64 provean, -5.15 CADD,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no extracardiac abnormalities

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, variant screening and classification, genic collapsing test, group statistical analysis

Variant: absent

ClinVar: absent

CAID: CA389051391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051391

gnomAD: absent

Case4: Male, 26 years report, Netherlands

CasePresentingHPOs: HP:0011663, HP:0011675, HP:0001279, HP:0005135, HP:0001707, HP:0004308, HP:0001711 (Right ventricular cardiomyopathy, Arrhythmia, Syncope, Abnormal T-wave, Abnormality of the right ventricle, Ventricular arrhythmia, Abnormality of the left ventricle)

HPOsFreeText: Positive EPS inducibility

CaseNotHPOs: HP:0001639, HP:0001635 (Hypertrophic cardiomyopathy, Congestive heart failure)

NotHPOsFreeText: ECG Depolarization abnormality, Cardiac transplant

CaseAddInfo:

CasePreviousTesting: No variants were in any of DSP, PKP2, DSG2, DSC2, and JUP. Patients were tested for variants in ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1.

CaseGenotypingMethod: 92 patients underwent panel sequencing of the specific genes listed above, and 45 were subject to Whole Exome Sequencing to locate variants. Afterwards, all variants were verified by PCR amplification and Sanger sequencing and filtered for pathogenicity.

Variant: NM_000257.3:c.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.4066G>A (p.Glu1356Lys)

ClinVar: 164294, https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

gnomAD: n/a

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.1051A>G (p.Lys351Glu)

ClinVar: 181335, https://www.ncbi.nlm.nih.gov/clinvar/variation/181335/

gnomAD: n/a

CaseA: Female, 49 yrs report

DiseaseEntity: Hypertrophic Cardiomyopathy (AD)

FamilyInfo: Has a monozygotic twin sister w/ same genotype and similar phenotype who lived far apart and had different living environments / life habits, Other family members were diagnosed with HCM afterwards and were genotype positive, See Figure 3 for pedigree

CasePresentingHPOs: HP:0001962, HP:0002875, HP:0001639, HP:0005110, HP:0031185, HP:0011713, HP:0001670, HP:0031295, HP:0030718, HP:0006683, HP:0001712 (Palpitations, Exertional dyspnea, Hypertrophic cardiomyopathy, Atrial fibrillation, Increased NT-proBNP level, Left bundle branch block, Asymmetric septal hypertrophy, Left atrial enlargement, Right atrial enlargement, Abnormal ventricular filling, Left ventricular hypertrophy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0031480 (Abnormal mitral valve leaflet morphology)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Elevated cardiac troponin T (cTnT) (19 ng/L; reference 0-14), Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (10,214 pg/mL; reference 0-88 pg/mL), Electrocardiogram (ECG) and multi-modality imaging

CaseGenotypingMethod: Whole exome sequencing was performed in the twins using Illumina Hiseq 2500. Low quality variations were filtered and analysed to find potentially pathogenic mutations. The findings were then confirmed using Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)

ClinVar: 164337 https://www.ncbi.nlm.nih.gov/clinvar/variation/164337/

gnomAD: Not in gnomAD

Case1: 18 year old male

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: parents and 2 siblings all phenotype negative for HCM, tested negative for the mutation

CasePresentingHPOs: HP:0001639, HP:0031992, HP:0031972, HP:0004755, HP:0004756

"Hypertrophic cardiomyopathy, Apical hypertrophic cardiomyopathy, presyncope, Supraventricular tachycardia, Ventricular tachycardia"

CasePreviousTesting: Authors simply state "on genetic testing"

Variant: NM_000257.4:c.1588A>G

ClinVar: 520309

CAID: CA028909

gnomAD: https://gnomad.broadinstitute.org/variant/14-23897094-T-C?dataset=gnomad_r2_1

Total Allele Frequency 0.000003980 South Asian 0.00003266

CaseIII-1: Male, China, Asian, 51 years report

CasePresentingHPOs: HP:0001962, HP:0100749, HP:0002094, HP:0500020, HP:0031185, HP:0004755, HP:0031295, HP:0011103 (Heart palpitations, Chest pain, Dyspnea, Abnormal cardiac biomarker test, Increased NT-proBNP level, Supraventricular tachycardia, Left atrial enlargement, Abnormality of the left ventricular outflow tract)

HPOsFreeText: Experienced palpitations for 9 years, Chest pain and mild dyspnea for 2 years, Slightly elevated cardiac troponin T level of 21.8 ng/L (normal 0 to 14 ng/L), Significantly elevated N-terminal pro-brain natriuretic peptide level of 537 pg./mL (normal 0 to 125 pg/mL), ECG showed non-specific ST_T change, Preserved biventricular systolic function, Severe LV outflow tract obstruction (peak aortic outflow velocity = 4.8 m/s, peak gradient = 92 mmHg), Proband had a sigmoid septum with LV outflow tract obstruction and LV mass index to body surface area (BSA) of 87.2 g/m2

CaseNotHPOs: HP:0001677 (Coronary artery disease)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was acquired from the proband and all surviving members of his extended family. These were all tested by a 117 gene screening panel that were connected to Cardiomyopathy. The results were confirmed by Sanger sequencing and the variants found were filtered for pathogenicity.

Variant: NM_000257.3:c.4130C>T (p.Thr1377Met)

ClinVar: 42992 https://www.ncbi.nlm.nih.gov/clinvar/variation/42992/

gnomAD: European (Non-Finnish) 8.791e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23887458-G-A

Segregation

Affected: 9

Unaffected: 17

Segregations: 23

PublishedLOD: N/A

eLOD: 6.92

AddSegInfo: 6 individuals died before this investigation so clinical data and phenotypes could not be collected, 10 individuals were genotype positive but phenotype negative

CaseIII-6: Female, 32 years report, 17 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Proband's son had the same variant; the father had echocardiograph results but was asymptomatic

CasePresentingHPOs: HP:0001639, HP:0002094, HP:0100749, HP:0001962, HP:0001279, HP:0030879 (Hypertrophic cardiomyopathy, Dyspnea, Chest pain, Palpitations, Syncope, Interlobular septal thickening on pulmonary HRCT)

HPOsFreeText: Septum thickness 25 mm, Left ventricle at 44 mm, Left atrium at 40 mm, Ejection fraction at 54%

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mutation is classified as de novo

CasePreviousTesting: See list of 26 genes under Target sequence capture sequencing

CaseGenotypingMethod: Genomic DNA was extracted from the proband and other family members. Afterwards, it was subject to PCR amplification and sequencing. Any variants found were confirmed with Sanger sequencing before being filtered for pathogenicity.

Variant: NM_000257.3:c.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: Not in gnomAD

Case309: Female, 0.01 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)

HPOsFreeText: Left Ventricular Ejection Fraction at 39%, LVDD-Z score at 1.08

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: Father and brother also have LVNC

CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.

Variant: NM_000257.3:c.1085T>G (p.Met362Arg)

CAID: CA389051391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1085T%3EG

gnomAD: Not in gnomAD

Case280: Male, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)

HPOsFreeText: Left Ventricular Ejection Fraction at 40%, LVDD-Z score at 2.16

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history, Died since publication

CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.

Variant listed as K542N, could be either CA389050168 or CA389050167.

Variant: NP_000248.2:p.Lys542Asn

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

JUP Variant

Variant: NM_002230.2:c.436G>A (p.Glu146Lys)

CAID: CA8565496 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002230.2:c.436G%3EA

gnomAD: African 6.353e-5, Overall 2.030e-5 https://gnomad.broadinstitute.org/variant/17-39925702-C-T

CaseMYH7-9: N/A

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

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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: European (Non-Finnish) 1.548e-5, Overall 7.070e-6 https://gnomad.broadinstitute.org/variant/14-23896866-C-T

CaseMYH7-28: 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.2782G>A (p.Asp928Asn)

ClinVar: 164313 https://www.ncbi.nlm.nih.gov/clinvar/variation/164313/

gnomAD: Not in gnomAD

CaseMYH7-20: 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.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

gnomAD: European (Non-Finnish) 1.416e-3, Overall 8.484e-4 https://gnomad.broadinstitute.org/variant/14-23892910-A-G

CaseMYH7-31: 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.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23900635-A-G

Case1: Male

DiseaseAssertion: HCM and LVNC

FamilyInfo: daughter with same diagnoses and variant 1

Variant1: NM_000257.4:c.1859T>C

ClinVar: not found

CAID: CA389049669

gnomAD: not found

Variant2: NM_000257.4:c.4377G>T

ClinVar: 43012

CAID: CA014901

gnomAD: https://gnomad.broadinstitute.org/variant/14-23886504-C-A?dataset=gnomad_r2_1

0.0005349 European (non Finnish)

CaseCM1762: Female, 12 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, Father shows positive for this variant with no symptoms while Mother shows negative for this variant with no symptoms

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.1845G>C (p.Lys615Asn)

CAID: CA389049696 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1845G%3EC

gnomAD: Not in gnomAD

CaseCM1824: Female, 13 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, Father afflicted with HCM and also positive for same 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.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: Not in gnomAD

CaseCM1811: Female, 15 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 shows positive for this variant with no symptoms while Father shows negative for this variant with no symptoms

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.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

gnomAD: European (Non-Finnish) 3.097e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Supplementary Data: S2 Table

Case 47: Spanish, 40yo, 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

Variant: NM_000257.3(MYH7):c.4066G>A (p.Glu1356Lys)

ClinVar: 164294, https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

gnomAD: n/a

Supplementary Data: S2 Table

Case 8: Spanish, 81yo, 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, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.3056C>A (p.Thr1019Asn)

ClinVar: 195720, https://www.ncbi.nlm.nih.gov/clinvar/variation/195720/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23892799-G-T

Case: Patient 7, male, 8yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0002650, HP:0030682, HP:0003458 (axial muscle weakness, scoliosis, left ventricular noncompaction, EMG: myopathic abnormalities)

HPOsFreeText: minicores present on muscle biopsy

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.3:c.5655+1G>A

CAID: CA389034770, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389034770

gnomAD: absent

Case: Patient 8, male, 35yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0002460, HP:0002650, HP:0003458 (foot drop, axial muscle weakness, distal muscle weakness, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: CK = 720U/l, neurogenic EMG, cores present on muscle biopsy

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant 1: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Variant 2: NM_000257.4(MYH7):c.4855G>A(p.Glu1619Lys)

ClinVar: 181268, https://www.ncbi.nlm.nih.gov/clinvar/variation/181268/

gnomAD: absent

Case II-3: Female, 40yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, reduced exercise capacity for 13yrs, mild heart failure symptoms, normal thickness of septum and left ventricle, 2 chambers of left ventricle have 18.5mm diameter of communication and they contract almost normally, left ventricle ventricle end-diastolic diameter = 74.3mm, left ventricular ejection fraction = 45%

CasePreviousTesting: same as proband

CaseGenotypingMethod: segregation analysis using the results from Sanger sequencing

Variant: NM_000257.3:c.998A>T

CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586

gnomAD: n/a

Case#: Case III-2, female, 74, early adulthood onset

DiseaseAssertion: Congenital Fiber Type Disproportion

FamilyInfo: Family A, late-onset weakness in her deceased mother (II-5) and maternal aunt (II-4), and lifelong weakness in her older sister (III-3)

CasePresentingHPOs: lower limb muscle weakness, gait disturbance, hearing loss, psoriasiform dermatitis, osteoarthritis, glaucoma, hypertension, muscle dystrophy, left ventricular diastolic dysfunction, hyperlordosis, genu recurvatum, proximal lower limb amyotrophy, foot dorsiflexor weakness, hip flexor weakness (HP:0007340, HP:0001288, HP:0000365, HP:0003765, HP:0002758, HP:0000501, HP:0000822, HP:0003560, HP:0025168, HP:0003307, HP:0002816, HP:0008956, HP:0009027, HP:0012515)

CaseHPOFreeText: Pes cavus and hammertor deformities, bilataeral steppage in gait,

CaseNotHPOs: N/A

CaseNotHPOFreeText: myotatic reflexes normal, ECG normal, normal NCS, no fibrillation potentials, sharp waves, or myotonic discharges

CasePreviousTesting: Analysis was negative for sequence variants affecting other congenital myopathy genes associated with CFTD pathology including ACTA1, RYR1, SEPN1, TPM2, and TPM3

CaseGenotypingMethod: neurological examination, serum creatine kinase (60 unit/L), nerve conduction studies, concentric needle electromyography (early recruitment of small polyphasic MUAP in diffuse pattern), electrocardiogram, echocardiogram, forced vital capacity (2.13% (76)), muscle biopsy, immunohistochemical analyses,

Variant: NM_000257.4(MYH7):c.484T>G (p.Tyr162Asp)

ClinVar: 525040 https://www.ncbi.nlm.nih.gov/clinvar/variation/525040/

CAID: N/A

gnomAD: absent

Case IV-1: Female, 10mo, carrier with no clinical manifestation

CaseHPOFreeText: interventricular septum = 4mm, posterior wall of left ventricle = 4mm, normal electrocardiogram

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

CasePT-35: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo: PT-36 and PT-37 are the proband's siblings in Family 18 with the same genotype

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

gnomAD: Ashkenazi Jewish 1.984e-4, Overall 7.953e-6 https://gnomad.broadinstitute.org/variant/14-23897796-C-A

CaseHCM085: 49 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001712, HP:0002875, HP:0011103, HP:0031295, HP:0001653, HP:0001279 (Left ventricular hypertrophy, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement, Mitral regurgitation, Syncope)

HPOsFreeText: Maximal LV thickness 19 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.1750G>A (p.Gly584Ser)

ClinVar: 42862 https://www.ncbi.nlm.nih.gov/clinvar/variation/42862/

gnomAD: Not in gnomAD

Case3: Male, 53 yrs diagnosis, Portugal

DiseaseAssertion: Dilated Cardiomyopathy

FamilyInfo: No family history

CasePresentingHPOs: HP:0001644, HP:0001635, HP:0011675, HP:0011713, HP:0012665, HP:0031192 (Dilated cardiomyopathy, Congestive heart failure, Arrhythmia, Left bundle branch block, Moderately reduced ejection fraction, Abnormal morphology of left ventricular trabeculae)

HPOsFreeText: Left ventricular end-diastolic diameter of 56 mm

CaseNotHPOs: HP:0002540, HP:0011706, HP:0001709, HP:0006682 (Inability to walk, Second degree atrioventricular block, Third degree atrioventricular block, Premature ventricular contractions)

NotHPOsFreeText: N/A

CasePreviousTesting: Proband has been studied before as part of FATIMA with general clinical assessment and cardiological investigations as well as exclusion criteria subject there. Tested genes include: LMNA, MYH7, MYBPC3, TNNT2, ACTA1, TPM1, CSRP3, TCAP, SGCD, PLN, MYL2, MYL3, TNNI3, TAZ, LDB3.

CaseGenotypingMethod: Blood samples were obtained and NGS was performed on a panel of 15 different genes covering the coding sequence and flanking exon/intron boundaries. Sanger sequencing was used to validate the variants and provide additional coverage. Variants were interpreted and filtered for pathogenicity.

CaseAddInfo: More info in 19044174 but paper is unavailable at this time

Variant: NM_000257.3:c.5623G>T (p.Val1875Phe)

CAID: CA389034842 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5623G%3ET

gnomAD: Not in gnomAD

Case1: 43 year old Caucasian female

DiseaseAssertion: LVHT, mild distal myopathy

FamilyInfo: LVHT was absent in all other family members who had undergone echocardiography, same MYH7 mutation detected in mother, who manifested with a mild distal myopathy

CasePresentingHPOs: HP:0001962, HP:0001279, HP:0004756, HP:0004308, HP:0012391

"Palpitations, Syncope, Ventricular tachycardia, Ventricular arrhythmia, Hyporeflexia of upper limbs"

CaseHPOFreeText: ectopic atrial tachycardia, mild weakness for foot extension on the right side, reduced Achilles tendon reflexes

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: n/a

Variant: NM_000257.4:c.5566G>A

ClinVar: 190403

CAID: CA347253

gnomAD: https://gnomad.broadinstitute.org/variant/14-23883305-C-T

0.000008795 European (non-Finnish)

Case#: D26, female, 54 years

DiseaseAssertion: FDCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

ClinVar: 181267 https://www.ncbi.nlm.nih.gov/clinvar/variation/181267/

CAID: N/A

gnomAD: absent

Case: Case report, female, 41yo

CasePresentingHPOs: HP:0001270, HP:0002094, HP:0007340, HP:0010535, HP:0002540, HP:0003323, HP:0002015, HP:0100749, HP:0001662, HP:0005952 (motor delay, dyspnea, lower limb weakness, sleep apnea, inability to walk, progressive muscle weakness, dysphagia, chest pain, bradychardia, decreased pulmonary function)

HPOsFreeText: non-smoker, onset of neuromuscular disorders in early childhood, written language delay, difficulty completing exercise, dyspnea and lower limb weakness presenting during patient's first pregnancy (33yo), required mechanical ventilation machine, symptoms of skeletal muscle disorder began after delivery of first child, unable to get up without assistance, unable to climb stairs, required use of cane, walker, then eventually a wheelchair, episodes of paralysis in lower limbs, normal tone/bulk of arm muscles but bilateral weakness in shoulders and upper limbs (MRC scale of 3/5), intact fine finger movements, down-going toes, reduced perception of vibration in lower limbs, needle EMG showed tendency of myotonic potentials, muscle biopsy of left quadricep showed features of end-stage process consistent with chronic myopathy (Fig. 2A-D), forced vital capacity = 27%, forced expiratory volume per second = 29%

CaseNotHPOs: HP:0001513, HP:0040129 (obese, abnormal nerve conduction velocity)

NotHPOsFreeText: pronator drift, sensory deficit, ocular muscle involvement

FamilyInfo: mother died at 66yo due to heart attack associated with non-compaction cardiomyopathy, daughter (11yo) has signs of muscle disorders, congenital muscular torticollis, excessive growing pains, and underdeveloped muscles in half of body

CaseGenotypingMethod: WES, variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.1370T>G (p.Ile457Arg)

ClinVar: 560881, https://www.ncbi.nlm.nih.gov/clinvar/variation/560881/

gnomAD: absent

MultipleGeneVariants:

(1) SNCB Variant

Variant: NM_003085.5(SNCB):c.368C>A (p.Pro123His)

ClinVar: 7026, https://www.ncbi.nlm.nih.gov/clinvar/variation/7026/

gnomAD: 0.0001929, https://gnomad.broadinstitute.org/variant/5-176048219-G-T

(2) GDF6 Variant:

Variant: NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)

ClinVar: 8371, https://www.ncbi.nlm.nih.gov/clinvar/variation/8371/

gnomAD: 0.001948, https://gnomad.broadinstitute.org/variant/8-97157413-G-T

Case1: deceased 16 year old female

DiseaseAssertion: HCM

FamilyInfo: 6 additional family members were found to be at risk for HCM

CasePresentingHPOs: HP:0001640, HP:0031319, HP:0002181

"Cardiomegaly, Cardiomyocyte hypertrophy, Cerebral edema

CaseHPOFreeText: Moderately enlarged heart, myocyte disarray, mild interstitial fibrosis

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: Whole Exome Next-Generation DNA Sequencing

Variant: NM_000257.4:c.746G>A

ClinVar: 14088

CAID: CA016781

gnomAD: not found

Case: Pedigree 3 proband, female, 3mo at diagnosis, North African and Jewish

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

HPOsFreeText: clinical severity: severe (fatal)

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: DCM CardioChip, included 19 genes known to cause DCM

Variant 1: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Variant 2: NM_000257.4(MYH7):c.4588C>T (p.Arg1530Ter)

ClinVar: 43029, https://www.ncbi.nlm.nih.gov/clinvar/variation/43029/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23886133-G-A

FamilyInfo: mother is of North African and Iraqi‐Jewish descent, while the father is of North African and Balkan Jewish descent, probands brother died at 3.5mo and also carried both variants, maternal cousin died of RCM in early childhood, maternal aunt carried p.R143W

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

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

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

gnomAD: n/a

Case8: Female, 12 yrs onset, Slovakia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Affected family members

CasePresentingHPOs: HP:0001639 (Hypertrophic Cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: Normal LV ejection fraction

CasePreviousTesting: ABCC9, ACTC1, ACTN2, ANKRD1, CASQ2, CAV3, CRYAB, CSRP3, CTF1, DES, DSC2, DSG2, DSP, DTNA, EMD, FHL2, GLA, JUP, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PKP2, PLN, PRKAG2, RBM20, RYR2, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL were all tested on NGS panel

CaseGenotypingMethod: Genomic DNA was extracted from whole blood and samples were purified and amplified. The coding exons for the above genes were enriched and sequenced. The resulting variants were analyzed and filtered for predicted pathogenicity.

CaseAddInfo: N/A

Variant: NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)

ClinVar: 14088 https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/

gnomAD: Not in gnomAD

MultipleGeneVariants

(1) DSP Variant

Variant: NM_004415.4(DSP):c.484C>G (p.Arg162Gly)

ClinVar: 546994 https://www.ncbi.nlm.nih.gov/clinvar/variation/546994/

gnomAD: 0.00006152, http://gnomad.broadinstitute.org/variant/6-7559520-C-G

Case#: Subject number 18, female, 40 years (diagnosis), 65 years (baseline visit), 64 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 13, male, 43 years (diagnosis), 47 years (baseline visit), 45 years (ERT), 44 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 21, female, 20 years (diagnosis), 52 years (baseline visit), 45 years (ERT), 39 (age at ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 8, female, 49 years (diagnosis), 59 years (baseline visit), 52 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 22(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 265 U/L (60-305 U/L is normal), AST: 92 U/L (22-71 U/L is normal), ALT: 46 U/L (7-50 U/L is normal), Hex4: 5.9 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 81.5 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 1.07 micromole/L/h and GAA activity #2 (NBS) 0.92 in dried blood spots (>2.10 micromole/L/h is normal). 1.60 in confirmatory testing (>3.88 is normal).

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

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 2(I), male, 10 days (start of ERT)

DiseaseAssertion: Infantile Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0200128 (biventricular hypertrophy), HP:0005165 (shortened PR interval), HP:0030234 (Highly elevated creatine kinase), HP:0001270 (motor delay)

CaseHPOFreeText: severe septal left ventricular hypertrophy and mildly hypertrophied right ventricle. CRIM positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 846 U/L (60–305 U/L is normal), AST: 189 U/L (30–100 U/L is normal), ALT: 91 U/L (7-50 U/L is normal), BNP: 1232.5 pg/mL (0.0–100.0 pg/mL), Hex4: 30.2 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 0.65 micromole/L/h and GAA activity #2 (NBS) 0.34 in dried blood spots (>2.10 micromole/L/h is normal). 0.4 in confirmatory testing (<3.88 is normal).

Variant 1: NM_000152.5(GAA):c.525delT

Variant 1 ClinVarID: 4033

Variant 1 CAid: CA220406

Variant 2: NM_000152.5(GAA):c.1694_1697delTCTC

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA658795263

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 25(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

glucosidase activity: GAA activity #2 (NBS) 0.95 in dried blood spots (>2.10 micromole/L/h is normal).

Variant 1: NM_000152.5(GAA):c.2238G>C

Variant 1 ClinVarID: 265160

Variant 1 CAid: CA8815665

Variant 2: NM_000152.5(GAA):c.2238G>C

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 2, male, symptoms noticed at 5 months

DiseaseAssertion: Pompe Disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639, HP:0001324 (hypertrophic cardiomyopathy, muscle weakness)

CaseHPOFreeText: Inability to swallow (needed NGT feeding until 21 months old)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: <1% normal GAA expression in fibroblast; after ERT treatment had 100% enzyme activity in cell lysates; unclear how patient was diagnosed

Variant 1: NM_000152.5:c.525delT

Variant 1 ClinVarID: 4033

Variant 1 CAid: CA220406

Variant 2: NM_000152.5:c.525delT

Variant 2 ClinVarID: 4033

Variant 2 CAid: CA220406

ParentalGenotype: Not provided

Case#: Subject number 1, male, 0 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: Family member with PD

CasePresentingHPOs: HP:0001638 (cardiomyopathy)

CaseHPOFreeText:

CaseNotHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: not asymptomatic, no biopsy

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.5 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.236_246delCCACACAGTGC (p.Pro79ArgfsTer13)

Variant 1 ClinVarID: 371302

Variant 1 CAid: CA16041880

Variant 2: NM_000152.5(GAA):c.236_246delCCACACAGTGC (p.Pro79ArgfsTer13)

Variant 2 ClinVarID: 371302

Variant 2 CAid: CA16041880

Zygosity: homozygous

ParentalGenotype: "the clinical information refers to parents as carriers of the disease, but the genetic study of his parents was not sent to us."

PreviouslyPublished: N/A

Case#: Subject number 3, female, 9 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: Family member with PD

CasePresentingHPOs:

CaseHPOFreeText: Asymptomatic

CaseNotHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy)

CaseNotHPOFreeText: no biopsy

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.15 mol/Lh in dried blood spots (normal range >0.75).

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

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1396_1397insG (p.Val466GlyfsTer?)

Variant 2 ClinVarID: ?

Variant 2 CAid: CA627699396

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient20: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1320_1322del (p.Met440del)

ClinVar: 526518, https://www.ncbi.nlm.nih.gov/clinvar/variation/526518/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

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

gnomAD: 0.0002146, http://exac.broadinstitute.org/variant/17-78092070-C-T