title: Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction.
abstract: BACKGROUND
  Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy.
  
  
  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.
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Wen-Yee
authors.initials: WY
authors.lastname: Choi
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Amy
authors.initials: A
authors.lastname: Dickson
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Martinez
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pignatelli
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.).
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.). agibbs@bcm.edu john.jefferies@cchmc.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: From the Human Genome Sequencing Center (M.N.B., M.W., H.D., D.M., E.B., R.G.), Department Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX (H.R.M., R.P., J.L.J.); Codified Genomics, LLC, Houston, TX (M.N.B.); Center for Human Disease Modeling, Duke University Medical Center, Durham, NC (E.E.D., N.K.); and Department of Cell Biology, Duke University, Durham, NC (W.-Y.C., A.D.). agibbs@bcm.edu john.jefferies@cchmc.org.
authors.forename: John L
authors.initials: JL
authors.lastname: Jefferies
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D024101:Mitochondrial Proteins / Q000235:genetics; D061087:NADP Transhydrogenase, AB-Specific / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D008164:Luminescent Proteins; D024101:Mitochondrial Proteins; D061087:NADP Transhydrogenase, AB-Specific; C556045:NNT protein, human
keywords: genetics; genomics; human; mutation; nonisolated left ventricular noncompaction