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

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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

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Exome
Mutation
Cardiomyopathies
Haploinsufficiency
Morpholinos
Frameshift Mutation
Inborn Genetic Diseases
Mitochondrial Proteins
Medical Genetics
Cardiomegaly
Zebrafish
Cardiac Myocytes
Genes
Alleles
Drive

All Science Journal Classification (ASJC) codes

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

Cite this

Loss of Function Mutations in NNT Are Associated with Left Ventricular Noncompaction. / Bainbridge, Matthew N.; Davis, Erica E.; Choi, Wen Yee; Dickson, Amy; Martinez, Hugo; Wang, Min; Dinh, Huyen; Muzny, Donna M.; Pignatelli, Ricardo; Katsanis, Nicholas; Boerwinkle, Eric; Gibbs, Richard A.; Jefferies, John.

In: Circulation: Cardiovascular Genetics, Vol. 8, No. 4, 25.08.2015, p. 544-552.

Research output: Contribution to journalArticle

Bainbridge, MN, Davis, EE, Choi, WY, Dickson, A, Martinez, H, Wang, M, Dinh, H, Muzny, DM, Pignatelli, R, Katsanis, N, Boerwinkle, E, Gibbs, RA & Jefferies, J 2015, 'Loss of Function Mutations in NNT Are Associated with Left Ventricular Noncompaction', Circulation: Cardiovascular Genetics, vol. 8, no. 4, pp. 544-552. https://doi.org/10.1161/CIRCGENETICS.115.001026
Bainbridge, Matthew N. ; Davis, Erica E. ; Choi, Wen Yee ; Dickson, Amy ; Martinez, Hugo ; Wang, Min ; Dinh, Huyen ; Muzny, Donna M. ; Pignatelli, Ricardo ; Katsanis, Nicholas ; Boerwinkle, Eric ; Gibbs, Richard A. ; Jefferies, John. / Loss of Function Mutations in NNT Are Associated with Left Ventricular Noncompaction. In: Circulation: Cardiovascular Genetics. 2015 ; Vol. 8, No. 4. pp. 544-552.
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