CaseIX: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM

CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.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

CaseVI: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM

CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.2389G>A (p.Ala797Thr)

ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/

gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894525-C-T

CaseBII-3: Female, 64 years diagnosis, Italy, Caucasian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: See Figure 1

CasePresentingHPOs: HP:0001639, HP:0002094 (Hypertrophic cardiomyopathy, Dyspnea)

HPOsFreeText: Max Left ventricular wall thickness of 19 mm, Left atrium diameter of 42 mm, Left ventricular ejection fraction of 64%

CaseNotHPOs: HP:0003115, HP:0011675 (Abnormal ECG, Arrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.

CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.

Variant: NM_000257.3:c.2631G>T (p.Met877Ile)

ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/

gnomAD: Not in gnomAD

CaseBII-1: Female, 64 years diagnosis, Italy, Caucasian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: See Figure 1

CasePresentingHPOs: HP:0005110, HP:0001639, HP:0004756, HP:0001712, HP:0005135, HP:0002094, HP:0001962, HP:0006682, HP:0001279, HP:0000821 (Atrial fibrillation, Hypertrophic cardiomyopathy, Ventricular tachycardia, Left ventricular hypertrophy, Abnormal T-wave, Dyspnea, Palpitations, Premature ventricular contractions, Syncope, Hypothyroidism)

HPOsFreeText: Widespread septal and apical late gadolinium enhancement, Max Left ventricular wall thickness of 20 mm, Left atrium diameter of 54 mm, Left ventricular ejection fraction of 56%, Apical aneurism, Latent tuberculosis

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.

CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.

Variant: NM_000257.3:c.2631G>T (p.Met877Ile)

ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/

gnomAD: Not in gnomAD

CaseBII-7: Male, 50 years diagnosis, Italy, Caucasian

DiseaseAssertion: Borderline Arrhythmogenic Cardiomyopathy

FamilyInfo: See Figure 1

CasePresentingHPOs: HP:0005133, HP:0006683 (Right ventricular dilatation, Abnormal ventricular filling)

HPOsFreeText: LVWT of 12 mm with an abnormal filling pattern, Mild right ventricular dilatation of 30  mm, Left atrium diameter at 45 mm, 62% ejection fraction

CaseNotHPOs: HP:0003115 (Abnormal ECG)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.

CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.

Variant: NM_000257.3:c.2631G>T (p.Met877Ile)

ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/

gnomAD: Not in gnomAD

Multiple Gene Variants

CTNNA3 Variant:

Variant: NM_013266.3:c.2296_2298delTTG (p.Leu766del)

ClinVar: 100657 https://www.ncbi.nlm.nih.gov/clinvar/variation/100657/

gnomAD: Not in gnomAD

Case KMP 22: Eastern Slovakia, Male, 21yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: negative family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, implantable cardioverter defibrillator

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 8: Eastern Slovakia, Male, 62yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 18: Eastern Slovakia, Female, 71yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I-II

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 1: Eastern Slovakia, Female, 39yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I,

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 7: Eastern Slovakia, Male, 36yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 4: Eastern Slovakia, Female, 69yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification II-III

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 16: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 39-40%, New York Heart Association Classification = I, implantable cardioverter defibrillator

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 8: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction , left ventricular ejection fraction = 55-60%,

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

MultipleGeneVariants:

(1) SCN5A Variant:

Variant: NM_198056.2(SCN5A):c.3784G>A (p.Gly1262Ser)

ClinVar: 9399, https://www.ncbi.nlm.nih.gov/clinvar/variation/9399/

gnomAD: 0.00002828, https://gnomad.broadinstitute.org/variant/3-38607956-C-T

Case KMP 11: Eastern Slovakia, Female, 57yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: positive family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case14: Male, 59 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One sibling had recurrent syncope and HCM with ICD implantation

CasePresentingHPOs: HP:0001639, HP:0001962, HP:0000822 (Hypertrophic cardiomyopathy, Palpitations, Hypertension)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

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

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

gnomAD: Not in gnomAD

Case12: Female, 60 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One sibling and one child died of SCD in their 30s, with child having confirmed HCM

CasePresentingHPOs: HP:0001639, HP:0030148 (Hypertrophic cardiomyopathy, Heart murmur)

HPOsFreeText: Mixed features of apical and classic HCM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

Variant: NM_000257.3:c.1273G>A (p.Gly425Arg)

ClinVar: 42834 https://www.ncbi.nlm.nih.gov/clinvar/variation/42834/

gnomAD: Not in gnomAD

Case15: Female, 48 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One parent died of cardiomyopathy/sudden death, one offspring had a heart murmur and found to have HCM

CasePresentingHPOs: HP:0001639, HP:0001279, HP:0005162, HP:0003546 (Hypertrophic cardiomyopathy, Syncope, Left ventricular failure, Poor exercise tolerance)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Heart transplantation done

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

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

Case13: Male, 57 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639, HP:0100749 (Hypertrophic cardiomyopathy, Chest pain)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

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

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

gnomAD: Not in gnomAD

Case: Pedigree 6 proband, 4yo at diagnosis

CasePresentingHPOs: HP:0001644, HP:0001657, HP:0001290, HP:0002033, HP:0001712, HP:0025169, HP:0001657 (dilated cardiomyopathy, prolonged QT interval, generalized hypotonia, poor suck, left ventricular hypertrophy, Left ventricular systolic dysfunction, prolonged QT interval)

HPOsFreeText: skeletal involvement, clinical severity: moderate to mild, bork at 39 weeks gestation, required tube feeding from 1wk-2yo, head lag, able to exert antigravity movements of her biceps, iliopsoas, and quadriceps, wiggle her fingers and toes, able to pedal her tricycle independently, globular left ventricle, end‐diastolic dimension: 3.14 cm, z‐score: 3.9, left ventricular diastolic dysfunction, fractional shortening of 25%, left ventricular EF of 46%

Skeletal muscle biopsy showed increased variations in fiber size with scattered small, round fibers, acceptable sarcomeric organization and striation with occasional fibers showing a spectrum of focal myofibrillary disorganization and irregular thickening of Z‐bands, absence of type 1 fibers, hypertrophy of type 2 fibers, normal motor and sensory responses of the left upper and lower limb muscles, small amplitude and short duration polyphasic motor units with early recruitment

CaseNotHPOs: HP:0009830, HP:0006802 (neuropathy, Abnormal anterior horn cell morphology)

CasePreviousTesting: sequencing of four genes associated with CFTD (SEPN1, TPM3, ACTA1, RYR1) were normal

CaseGenotyping: karyotype, chromosomal microarray, MYH7 sequencing

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

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

gnomAD: n/a