Supplementary Material 4

Case M-28: 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.2770G>A (p.Glu924Lys)

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

gnomAD: n/a

Supplementary Material 4

Case M-21: 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:c.2302_2310del

CAID: CA913184893, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184893

gnomAD: n/a

Supplementary Material 4

Case M-12: 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.1988G>A (p.Arg663His)

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

gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Supplementary Material 4

Case M-31: 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.4721G>A (p.Arg1574Gln)

ClinVar: 228912, https://www.ncbi.nlm.nih.gov/clinvar/variation/228912/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23885445-C-T

Supplementary Material 4

Case M-11: 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.1988G>A (p.Arg663His)

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

gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Supplementary Material 4

Case M-27: 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.2770G>A (p.Glu924Lys)

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

gnomAD: n/a

Supplementary Material 4

Case M-3: 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.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Supplementary Material 4

Case M-5: 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.1012G>A (p.Val338Met)

Clinvar: 164381, https://www.ncbi.nlm.nih.gov/clinvar/variation/164381/

gnomAD: n/a

Supplementary Material 4

Case M-17: 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.2207T>C (p.Ile736Thr)

ClinVar: 164342, https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: n/a

Supplementary Material 4

Case M-13: 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.2011C>T (p.Arg671Cys)

ClinVar: 164350, https://www.ncbi.nlm.nih.gov/clinvar/variation/164350/

gnomAD: n/a

Supplementary Material 4

Case M-7: 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 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: n/a

Supplementary Material 4

Case M-24: 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-4: 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.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Supplementary Material 4

Case M-10: 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-6: 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 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: n/a

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 Material 4

Case M-16: 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.2156G>A (p.Arg719Gln)

ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: n/a

Supplementary Material 4

Case M-29: 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-20: 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.2221G>T (p.Gly741Trp)

ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: n/a

Supplementary Material 4

Case M-19: 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.2221G>T (p.Gly741Trp)

ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: n/a

Supplementary Material 4

Case M-1: 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 1: NM_000257.3:c.175G>A

CAID: CA029319, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA029319

gnomAD: 0.000007955, https://gnomad.broadinstitute.org/variant/14-23902767-C-T

Variant 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: n/a

Supplementary Material 4

Case M-18: 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.2221G>T (p.Gly741Trp)

ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: n/a

Supplementary Material 4

Case M-2: 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.611G>A (p.Arg204His)

ClinVar: 43095, https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23900998-C-T

Supplementary Material 4

Case M-8: 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.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

Supplementary Material 4

Case M-25: 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:c.2596T>C

CAID: CA389048059, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048059

gnomAD: n/a

Supplementary Material 4

Case M-14: 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.2155C>T (p.Arg719Trp)

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

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A

Supplementary Material 4

Case M-22: 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.2333A>G (p.Asp778Gly)

ClinVar: 14100, https://www.ncbi.nlm.nih.gov/clinvar/variation/14100/

gnomAD: n/a

Supplementary Material 4

Case M-15: 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.2155C>T (p.Arg719Trp)

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

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A

Case III-3: Male, 27yo, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0005135 (exertional dyspnea, chest pain, ST segment depression, abnormal T wave)

CaseHPOFreeText: abnormal Q wave, interventricular septum = 20mm, posterior wall of left ventricle = 7mm

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

Case II-9: Female, 46yo, diagnosed at 14yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0005135, HP:0011713 (exertional dyspnea, chest pain, ST segment depression, abnormal T wave, left bundle branch block)

CaseHPOFreeText: abnormal Q wave, Wide QRS, interventricular septum = 13mm, posterior wall of left ventricule = 9mm

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

Case III-15: Male, 18yo, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0012250 (ST segment depression

CaseHPOFreeText: abnormal Q wave, interventricular septum = 15mm, posterior wall of left ventricle = 9mm

CaseNotHPOs: HP:0005135 (abnormal T wave)

CaseNotHPOFreeText: no clinical manifestations

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

Case III-4: proband, Chinese, male, 46yo, diagnosed with HCM at 18yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0010872, HP:0011713 (exertional dyspnea, chest pain, ST segment depression, T wave inversion, left bundle branch block)

CaseHPOFreeText: electrocardiography showed abnormal Q wave, atrium expansion, ventricular septum thickness = 13mm, left ventricular posterior wall = 10mm, left ventricular end-diastolic diameter = 52mm, left ventricular ejection fraction = 55%, small amount of tricuspid regurgitation

FamilyInfo: study assessed 3 generations of this family (22 individuals), all participants were genotyped, 8 family members were carriers of variant (p.Asn391Thr) 6 of which were diagnosed with HCM, four individual in the family died (3 of which had been diagnosed with HCM)

CasePreviousTesting: Full testing of 7 sarcomere genes (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional gene testing (MYH6, TTN, TNNC1, PRKAG2, LAMP2, GLA, CSPR3, MYOZ2, JH2, ACTN2, CAV3, LDB3, VCL, PLN, MYPN, NEXN, CALR3, ANKRD1), electrocardiogram, echocardiogram

CaseGenotypingMethod: genomic DNA collected from peripheral venous blood leukocytes, high-throughput sequencing used to sequence 26 genes (exons and 5bps of upstream and downstream intron sequences), amplified via PCR

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

Case III-11: Male, 32yo, Chinese, unknown age of diagnosis

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0005135 (abnormal T wave)

CaseHPOsFreeText: ventricular septum thickness = 16mm, posterior wall of left ventricle = 10mm

CaseNotHPOs: HP:0012250 (ST segment depression)

CaseNotHPOsFreeText: no clinical manifestation, abnormal Q wave

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

Case III-16: Male, 17yo, Chinese, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0100576, HP:0012250 (exertional dyspnea, chest pain, amaurosis fugax, ST segment depression)

CaseHPOFreeText: abnormal Q wave, interventricular septum = 21mm, posterior wall of left ventricle = 10mm, outflow obstruction

CaseNotHPOs: HP:0005135 (abnormal T wave)

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

Case: Male, born at 38 weeks gestation

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0030718, HP:0001667, HP:0002092, HP:0001670, HP:0200128 (enlarged right atrium, right ventricular hypertrophy, pulmonary hypertension, asymmetric septal hypertrophy, biventricular hypertrophy)

CaseHPOFreeText: birth weight = 3.283kg, apgar scores = 8,9, asymmetric septal hypertrophy of atrioventricular septum without outflow tract obstruction or myocardial scarring, confirmed diagnosis of HCM at 6mo

CaseNotHPOs: HP:0011611, HP:0001653, HP:0004308, HP:0005115 (aortic obstruction, mitral valve insufficiency, ventricular arrhythmia, supraventricular arrhythmia)

FamilyInfo: Both parents and only sibling underwent genetic testing, the father and brother harbored the same variant as the patient (p.Ala1328Thr), this variant was absent in the mother. Father (36yo) and brother (5yo) had normal echocardiograms.

CasePreviousTesting: fetal echocardiography at 32wks, postnatal echocardiography, routine cardiac follow-up at 6mo, cardiac MRI, 24hr Holter monitor, Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (CAV3, MTTG, MTTI, MTTK, MTTQ, TNNC1, TTR, PKRAG2, LAMP2, GLA)

CaseGenotypingMethod: blood and buccal cell samples collected from patient, coding regions and splice junctions of 18 genes were enriched with a proprietary targeted capture system by GeneDx, these then underwent NextGen sequencing, capillary sequencing used to confirm potentially pathogenic variants

Variant: NM_000257.3(MYH7):c.3982G>A (p.Ala1328Thr)

ClinVar: 42985, https://www.ncbi.nlm.nih.gov/clinvar/variation/42985/

gnomAD: 0.00002154, https://gnomad.broadinstitute.org/variant/14-23887606-C-T

InheritancePattern: autosomal dominant

Case III-4: Female, 4yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: myocardium lesion, suspected double-chambered left ventricle, asymptomatic, normal thickness of septum and left ventricle, fibromuscular tissues left ventricular apex, left ventricle ventricle end-diastolic diameter = 38.4mm, left ventricular ejection fraction = 64%

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 III-1: Male, 11yo, proband, died at 12yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0002018, HP:0000969, HP:0003388, HP:0001640, HP:0002240, HP:0002240, HP:0005135, HP:0031295 (nausea, edema, fatigability, cardiomegaly, hepatomegaly, left ventricular hypertrophy, abnormal T-wave, left atrial enlargement)

CaseHPOFreeText: inability to lie down, double chambered left ventricle, protrusion of precordium, soft heart sounds, grade 3/6 systolic murmur at the cardiac apex, liver enlarged to 3cm below right costal margin, left ventricle divided into apical and basal chambers by an incomplete fibromuscular septum, basal chamber was enlarged (ball-shaped) and had end-diastolic diameter of 80.7mm, impaired contraction of of left ventricular wall and septum, reduction of left ventricular ejection fraction = 35%, diameter of communication between 2 chambers of left ventricle = 16.0mm, the apical chamber of the left ventricle had a thinning wall, relative dullness of cardiac enlargement, normal thickness of septum and left ventricular wall, upper and middle section of ventricular septum expanded to right ventricle, died due to multiple system organ failure

FamilyInfo: 8 family members with double-chambered left ventricles

CasePreviousTesting: transthoracic echocardiography, ECG, cardiac MRI

CaseGenotypingMethod: WES, Affymetrix Cytoscan 750K Array to check potential candidate copy number variations, 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 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 I-2: Female, 66yo, suspected to be the founder of the variant

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001635 (heart failure)

CaseHPOFreeText: suspected double-chambered left ventricle

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 II-5: Female, 35yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0003388, HP:0001712 (fatigability, left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, normal thickness of septum and left ventricular wall, 2 chamber of left ventricle have 14.2mm diameter of communication and they both contract normally, left ventricle ventricle end-diastolic diameter = 59.9mm, left ventricular ejection fraction = 50%

CasePreviousTesting: same as proband

CaseGenotypingMethod: WES, 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 III-3: Female, 6yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, asymptomatic, normal thickness of septum and left ventricle, left ventricle ventricle end-diastolic diameter = 53.5mm, left ventricular ejection fraction = 64%

CasePreviousTesting: same as proband

CaseGenotypingMethod: Affymetrix Cytoscan 750K Array to check potential candidate copy number variations, 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: proband, 9mo at presentation

DiseaseAssertion: Idiopathic dilated cardiomyopathy

CasePresentingHPOs: HP:0001635, HP:0001695, HP:0001263, HP:0007018, HP:0007018, HP:0002059, HP:0031332 (congestive heart failure, cardiac arrest, global developmental delay, attention deficit, autism, cerebral atrophy, myocyte degeneration)

CaseHPOFreeText: had transvenous pacemaker for complete heart block and left ventricular assist device, ABO-incompatible heart transplant at 1yo, walked at 2.5yo, sensory and behavioral deficits, suspected mitochondrial disorder

FamilyInfo: Parents underwent Sanger Sequencing to confirm variant was de novo in proband (Fig. 2)

CasePreviousTesting: MRI, metabolic evaluation, Full testing (MYPBC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TruSight One Gene List)

CaseGenotypingMethod: chromosomal microarray, trio analysis with fluorescent in situ hybridization, next-gen sequencing of 4813 genes (TruSight One Sequencing Panel), Sanger Sequencing

Variant: NM_000257.3(MYH7):c.2513C>T (p.Pro838Leu) (previously reported as de novo, PMID: 18380764)

ClinVar: 42910, https://www.ncbi.nlm.nih.gov/clinvar/variation/42910/

gnomAD: n/a

MultipleGeneVariants:

(1) NRXN1 Variant:

Variant: 181,000bp copy number loss within chr 2:6.3, build NCBI 37/hg19 (from position 51201593-51382885)

CaseIII-1: 53 years old at time of report

DiseaseAssertion: Laing distal myopathy

FamilyInfo: Mutation in the MYH7 gene was cosegregated within the family members. In this family, the mutation segregated to the three affecteds, but not to any of the six unaffecteds

CasePresentingHPOs: HP:0008997, HP:0008994, HP:0009053, HP:0008959, HP:0100595

"Proximal muscle weakness in upper limbs, Proximal muscle weakness in lower limbs, Distal lower limb muscle weakness, Distal upper limb muscle weakness, camptocormia"

CaseHPOFreeText: hanging big toes and early involving neck flexors at the age of 8 years, atrophies in both sternocleidomastoid muscles, posture showed asymmetry of muscle atrophy, shoulder elevation

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Level of serum creatine kinase was 534 IU/L (normal range < 185 IU/L). Echocardiogram and serum cardiac enzyme activity were normal. Needle electromyography showed generalized myopathic patterns, while nerve conduction studies were normal. "several functionally significant variants were identified from myopathy-related genes"

GenotypingMethod: whole exome sequencing, capillary DNA sequencing, and in silico analysis

Variant: NM_000257.3:c.4315G>C

ClinVar: 190404

CAID: CA347256

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

Case: VWD cohort index patients (IPs)

DiseaseAssertion: congenital bleeding disorder

FamilyInfo: Six index patients (IPs), from VWD cohort of patients of Germany and Pakistan

ParentalGenotype(s):

CasePresentingHPOs: HP:0000006

CaseHPOFreeText: IP1 (VWF:Ag (IU/dl)=12), IP2 (WF:Ag (IU/dl)=1), IP3 (VWF:Ag (IU/dl)=29), IP4 (VWF:Ag (IU/dl)= 1), IP5 (VWF:Ag (IU/dl)=35), IP6 (VWF:Ag (IU/dl)= 1)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Not provided

PreviouslyPublished:

Gene: VWF

Variant: IP1 c.164G>A (p.Gly55Glu), IP2 c.4019T>G, c.257T>A (p.Leu1340Arg , p.Val86Glu), IP3 c.571T>C (p.Trp191Arg), IP4 c.3797C>T, c.631A>G (p.Pro1266Leu, p.Asn211Asp) , IP5 c.3931C>T, c.1001G>A (p.Gln1311X,p.Gly334Glu) , IP6 c.2561G>A, c.1824C>G (p.Arg854Gln , p.Cys608Trp)

HGVS: NM_000552.4 and NP_000543.2

ClinVarID:https://www.ncbi.nlm.nih.gov/clinvar/?term=VWF%5Bgene%5D&redir=gene

CAID: 00311186–00311190

gnomAD:n/a

Case: 24-year-old Caucasian woman with a rare variety of type 2M VWD

DiseaseAssertion: 2M VWD

FamilyInfo: family history was negative for easy bruisability, bleeding, or clotting disorder but maternal grandmother had lung cancer.

CaseNOTHPOFreeText: Von Willebrand factor antigen 45% on 9/12/17 and 37% on 9/19/17 with the ratio of VWF activity to the antigen is less than 0.7

ParentalGenotype(s):Unknown

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0000978 (Bruising susceptibility).

**CaseHPOFreeText: ** loss of weight over the last six months, The complete blood count, comprehensive metabolic panel, factor VIII, prothrombin time and partial thromboplastin time, D-Dimer, and antithrombin activity were normal. Her von Willebrand factor activity was much lower compared to the antigen.

CasePreviousTesting: None

GenotypingMethod: Patient have not been genotyped

PreviouslyPublished: N/A

Variant: N/A

ClinVarID: N/A

gnomAD: N/A

**Gene: ** VWF Inheritance mode autosomal dominant variety with normal, high molecular weight multimers

CRX