학술논문
Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.
Document Type
Academic Journal
Author
Blue EE; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.; White JJ; Invitae, San Francisco, CA, USA.; Dush MK; Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.; Gordon WW; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Wyatt BH; Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.; White P; Institute for Genomic Medicine, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Marvin CT; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Helle E; New Children's Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland.; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Ojala T; New Children's Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland.; Priest JR; Stanford University School of Medicine, Lucile Packard Children's Hospital, Stanford, CA, USA.; Jenkins MM; National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.; Almli LM; National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.; Reefhuis J; National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.; Pangilinan F; Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.; Brody LC; Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.; McBride KL; Center for Cardiovascular Research, Nationwide Children's Hospital, and Division of Genetic and Genomic Medicine, Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Garg V; Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Shaw GM; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Romitti PA; Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA.; Nembhard WN; University of Arkansas for Medical Sciences, Little Rock, AR, USA.; Browne ML; Birth Defects Registry, New York State Department of Health, Albany, NY, USA.; Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, USA.; Werler MM; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.; Kay DM; Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA.; Mital S; Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.; Chong JX; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Nascone-Yoder NM; Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.; Bamshad MJ; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Source
Publisher: Elsevier Inc Country of Publication: United States NLM ID: 101772885 Publication Model: eCollection Cited Medium: Internet ISSN: 2666-2477 (Electronic) Linking ISSN: 26662477 NLM ISO Abbreviation: HGG Adv Subsets: MEDLINE
Subject
Language
English
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10 -5 ), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model ( Xenopus laevis ) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2 707C>T and CAPN2 1112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.
Competing Interests: M.J.B. and J.X.C. are the editor-in-chief and deputy editor, respectively, of Human Genetics and Genomics Advances and were recused from the editorial handling of this article. J.J.W. is an employee and shareholder of Invitae. M.J.B. is chair of the Scientific Advisory Board of GeneDx. S.M. is on the Hypertrophic Cardiomyopathy Advisory Board of Bristol-Myers Squibb.
(© 2023 The Author(s).)
Competing Interests: M.J.B. and J.X.C. are the editor-in-chief and deputy editor, respectively, of Human Genetics and Genomics Advances and were recused from the editorial handling of this article. J.J.W. is an employee and shareholder of Invitae. M.J.B. is chair of the Scientific Advisory Board of GeneDx. S.M. is on the Hypertrophic Cardiomyopathy Advisory Board of Bristol-Myers Squibb.
(© 2023 The Author(s).)