title: Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction.
abstract: BACKGROUND
  The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation.
  
  
  RESULTS
  Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ≤40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function.
  
  
  CONCLUSIONS
  In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively.
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Jeanne L
authors.initials: JL
authors.lastname: Theis
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Eckloff
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Muhammad Y
authors.initials: MY
authors.lastname: Qureshi
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: O'Leary
authors.affiliation: From the Cardiovascular Genetics Research Laboratory (J.L.T., T.M.O.), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.Y.Q., P.W.O'L., T.M.O.), Division of Cardiovascular Diseases, Department of Internal Medicine (T.M.O.), Departments of Health Sciences Research and Biomedical Statistics and Informatics (M.T.Z., J.M.E.), Medical Genome Facility (B.W.E., E.D.W.), and Department of Biochemistry and Molecular Biology (E.D.W.), Mayo Clinic, Rochester, MN. olson.timothy@mayo.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
mesh_terms: D024722:Cardiac Myosins / Q000737:chemistry / Q000235:genetics*; D004452:Echocardiography; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA / Q000379:methods; D013318:Stroke Volume / Q000235:genetics* / Q000502:physiology
chemical_list: C094239:MYH6 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: genomics; heart defects, congenital; heart failure; hypoplastic left heart syndrome; missense mutations; myosin heavy chains