Case1: Male, 50 years report, Netherlands

CasePresentingHPOs: HP:0011663, HP:0011675, HP:0001279, HP:0005135, HP:0001707, HP:0001711, HP:0004308, HP:0001635 (Right ventricular cardiomyopathy, Arrhythmia, Syncope, Abnormal T-wave, Abnormality of the right ventricle, Abnormality of the left ventricle, Ventricular arrhythmia, Congestive heart failure)

HPOsFreeText: Positive EPS inducibility, Cardiac transplant required

CaseNotHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

NotHPOsFreeText: N/A

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.2541_2549del (p.Lys847_Ala850delinsAsn)

CAID: CA913184863 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184863

gnomAD: Not in gnomAD

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

Case3: Male, 37 years report, Netherlands

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

HPOsFreeText: Positive EPS inducibility

CaseNotHPOs: HP:0001639, HP:0001635, HP:0001711 (Hypertrophic cardiomyopathy, Congestive heart failure, Abnormality of the left ventricle)

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.5536C>T (p.Arg1846Cys)

ClinVar: 161321 https://www.ncbi.nlm.nih.gov/clinvar/variation/161321/

gnomAD: East Asian 5.441e-5, Overall 1.208e-5 https://gnomad.broadinstitute.org/variant/14-23884227-G-A

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