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; National Birth Defects Prevention Study; University of Washington Center for Mendelian Genomics; Seema Mital; Jessica X Chong; Nanette M Nascone-Yoder; Michael J Bamshad

doi:10.1016/j.xhgg.2023.100232

Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome

HGG Adv. 2023 Aug 12;4(4):100232. doi: 10.1016/j.xhgg.2023.100232. eCollection 2023 Oct 12.

Authors

Elizabeth E Blue^{1

2}, Janson J White³, Michael K Dush⁴, William W Gordon⁵, Brent H Wyatt⁴, Peter White⁶, Colby T Marvin⁵, Emmi Helle^{7

8}, Tiina Ojala⁷, James R Priest⁹, Mary M Jenkins¹⁰, Lynn M Almli¹⁰, Jennita Reefhuis¹⁰, Faith Pangilinan¹¹, Lawrence C Brody¹¹, Kim L McBride¹², Vidu Garg¹³, Gary M Shaw¹⁴, Paul A Romitti¹⁵, Wendy N Nembhard¹⁶, Marilyn L Browne^{17

18}, Martha M Werler¹⁹, Denise M Kay²⁰; National Birth Defects Prevention Study; University of Washington Center for Mendelian Genomics; Seema Mital²¹, Jessica X Chong^{2

5}, Nanette M Nascone-Yoder⁴, Michael J Bamshad^{2

5

22}

Affiliations

¹ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
² Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
³ Invitae, San Francisco, CA, USA.
⁴ Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.
⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁶ Institute for Genomic Medicine, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
⁷ New Children's Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland.
⁸ Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Stanford University School of Medicine, Lucile Packard Children's Hospital, Stanford, CA, USA.
¹⁰ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹¹ Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
¹² 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.
¹³ Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
¹⁴ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA.
¹⁶ University of Arkansas for Medical Sciences, Little Rock, AR, USA.
¹⁷ Birth Defects Registry, New York State Department of Health, Albany, NY, USA.
¹⁸ Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, USA.
¹⁹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²⁰ Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA.
²¹ Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
²² Department of Genome Sciences, University of Washington, Seattle, WA, USA.

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.

Keywords: Xenopus; association; congenital heart defect; development; exome sequencing; frog; oligogenic.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Alleles
Animals
Aorta
Calpain / genetics
Cerebral Ventricles
Humans
Hypoplastic Left Heart Syndrome* / genetics

Substances

Calpain
CAPN2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding