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

Matthew N. Bainbridge, Erica Ellen Davis, Wen Yee Choi, Amy Dickson, Hugo R. Martinez, Min Wang, Huyen Dinh, Donna M. Muzny, Ricardo Pignatelli, Elias Nicholas Katsanis, Eric Boerwinkle, Richard A. Gibbs*, John L. Jefferies

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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 data from multiple members from 5 families with LVNC. In 4 of 5 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 7 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, probably 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 whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.

Original languageEnglish (US)
Pages (from-to)544-552
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number4
DOIs
StatePublished - Aug 25 2015

Keywords

  • genetics
  • genomics
  • human
  • mutation
  • nonisolated left ventricular noncompaction

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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