HGG Advances (Oct 2023)
Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome
- Elizabeth E. Blue,
- Janson J. White,
- Michael K. Dush,
- William W. Gordon,
- Brent H. Wyatt,
- Peter White,
- Colby T. Marvin,
- Emmi Helle,
- Tiina Ojala,
- James R. Priest,
- Mary M. Jenkins,
- Lynn M. Almli,
- Jennita Reefhuis,
- Faith Pangilinan,
- Lawrence C. Brody,
- Kim L. McBride,
- Vidu Garg,
- Gary M. Shaw,
- Paul A. Romitti,
- Wendy N. Nembhard,
- Marilyn L. Browne,
- Martha M. Werler,
- Denise M. Kay,
- Seema Mital,
- Jessica X. Chong,
- Nanette M. Nascone-Yoder,
- Michael J. Bamshad
Affiliations
- Elizabeth E. Blue
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Corresponding author
- Janson J. White
- Invitae, San Francisco, CA, USA
- Michael K. Dush
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
- William W. Gordon
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Brent H. Wyatt
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
- Peter White
- Institute for Genomic Medicine, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Colby T. Marvin
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Emmi Helle
- 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
- Tiina Ojala
- New Children’s Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
- James R. Priest
- Stanford University School of Medicine, Lucile Packard Children’s Hospital, Stanford, CA, USA
- Mary M. Jenkins
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Lynn M. Almli
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Jennita Reefhuis
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Faith Pangilinan
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Lawrence C. Brody
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Kim L. McBride
- 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
- Vidu Garg
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Gary M. Shaw
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Paul A. Romitti
- Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
- Wendy N. Nembhard
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Marilyn L. Browne
- 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
- Martha M. Werler
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
- Denise M. Kay
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
- Seema Mital
- Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Jessica X. Chong
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA
- Nanette M. Nascone-Yoder
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
- Michael J. Bamshad
- 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
- Journal volume & issue
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Vol. 4,
no. 4
p. 100232
Abstract
Summary: 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 CAPN2707C>T and CAPN21112C>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.
