truncations cause arrhythmogenic right ventricular cardiomyopathy.

Title truncations cause arrhythmogenic right ventricular cardiomyopathy.
Publication TypeJournal Article
Year of Publication2020
AuthorsBrun, F, Gigli, M, Graw, SL, Judge, DP, Merlo, M, Murray, B, Calkins, H, Sinagra, G, Taylor, MRg, Mestroni, L, James, CA
JournalJ Med Genet
Date Published2020 04
KeywordsAdult, Aged, Arrhythmogenic Right Ventricular Dysplasia, Female, Filamins, Genetic Predisposition to Disease, Genetic Testing, Heart Ventricles, Humans, Male, Middle Aged, Mutation, Phenotype

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.

OBJECTIVE: Filamin C gene truncations () have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that could be a novel gene associated with ARVC.

METHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for variants. Available family members were tested for cosegregation.

RESULTS: We identified two unique variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.

CONCLUSION: The identification of as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC disease genes for this disorder. Our findings should prompt inclusion of genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

Alternate JournalJ Med Genet
PubMed ID31924696
PubMed Central IDPMC7539291
Grant ListR01 HL147064 / HL / NHLBI NIH HHS / United States
UL1 TR002535 / TR / NCATS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R01 HL069071 / HL / NHLBI NIH HHS / United States
M01 RR000051 / RR / NCRR NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States
R01 HL109209 / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
R01 HL116906 / HL / NHLBI NIH HHS / United States
17GRNT33670495 / AH / American Heart Association-American Stroke Association / United States