Journal article
Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome
HGG advances, Vol.4(4), 100232
10/12/2023
DOI: 10.1016/j.xhgg.2023.100232
PMCID: PMC10474499
PMID: 37663545
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 CAPN2 (p=1.8x10-5), 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, 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.
Details
- Title: Subtitle
- Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome
- Creators
- Elizabeth E. BlueJanson J. WhiteMichael K. DushWilliam W. GordonBrent H. WyattPeter WhiteColby T. MarvinEmmi HelleTiina OjalaJames R. PriestMary M. JenkinsLynn M. AlmliJennita ReefhuisFaith PangilinanLawrence C. BrodyKim L. McBrideVidu GargGary M. ShawPaul A. RomittiWendy N. NembhardMarilyn L. BrowneMartha M. WerlerDenise M. KaySeema MitalJessica X. ChongNanette M. Nascone-YoderMichael J. Bamshad
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.4(4), 100232
- DOI
- 10.1016/j.xhgg.2023.100232
- PMID
- 37663545
- PMCID
- PMC10474499
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Language
- English
- Electronic publication date
- 08/2023
- Date published
- 10/12/2023
- Academic Unit
- Epidemiology; Biostatistics
- Record Identifier
- 9984455616202771
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