Loss of Function Mutations in NNT Are Associated with Left Ventricular Noncompaction

BACKGROUND: Left ventricular noncompaction (LVNC) is an autosomal dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy. METHODS AND RESULTS: Here, we generated whole exome sequence (WES) data from multiple members from five families with LVNC. In four out of five families, the candidate causative mutation segregates with disease in known LVNC genes MYH7 and TPM1. Subsequent sequencing of MYH7 in a larger LVNC cohort identified seven novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in NNT, a nuclear encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of NNT in additional LVNC families identified a second likely pathogenic missense allele. Suppression of nnt in zebrafish caused early ventricular malformation and contractility defects, likely driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism. CONCLUSIONS: Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of WES with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.