KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

BACKGROUND: Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. METHODS AND RESULTS: By genome‐wide scan with microsatellite markers and genetic linkage analysis in a 4‐generation family inflicted with autosomal‐dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1–q13.3, a 4.77‐cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2‐point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole‐exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7. Add, the E144X‐mutant KLF13 showed a defect in intracellular distribution. CONCLUSIONS: This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.