Objectives: Cardiomyopathies are diseases of heart muscle caused by mutations in cytoskeletal genes. Disease severity and penetrance vary greatly among patients carrying the same mutation(s) and single-gene variants often do not reliably predict cardiomyopathy phenotypes.
Background: The chromosome 10q21-q23 locus was previously associated to familial dilated cardiomyopathy (DCM), arrhythmias, heart failure, Wolff-Parkinson-White (WPW) syndrome, mitral valve prolapse (MVP) and/or mitral regurgitation (MR). However, the exact variants responsible for heterogeneous DCM and arrhythmia phenotypes remained unknown.
Methods: A large family of 62 members was re-studied using whole exome and direct sequencing. Phenotypegenotype correlation and systems genetics analysis were performed.
Results: We identified missense KCNMA1-M744T, ANXA11-I457V, and DYDC2-P123R variants at 10q21-q23. The proband and ten family members carried ANXA11-I457V and DYDC2-P123R identified in cis (digenicheterozygosity). Seven digenic carriers were affected including DCM (n=3), heart failure (n=1), left ventricular dysfunction (n=3), arrhythmia (n=2), MVP (n=2) and MR (n=3). A single KCNMA1-M744T variant was identified in 11 individuals, including 4 affected with MVP or MR (n=4), ventricular arrhythmia (n=2), and WPW (n=1). All three variants were identified in three family members and all were affected. Rare variants in cardiomyopathy-related genes such as CORIN-I52V, TTN-S21630P, TRPM7-Y537H, OTX1-H301del and FLNC-N47Swere identified in affected individuals.
Conclusion: This study facilitated the family-based predictive and personalized approach in identifying disease causative basis in patients with familial DCM and their relatives “at risk”. Different variant combinations of transKCNMA1-M744T, cis-ANXA11-I457V and DYDC2-P123R identified at 10q21-q23 underlie the clinical heterogeneity of familial DCM. Rare variants identified beyond the 10q21-q23 were predicted to modify the function of KCNMA1, ANXA11, andDYDC2 that may serve as the genetic modifiers in intra- and inter-familial phenotypic variability