2023 journal article
Rare variants in <i>CAPN2</i> increase risk for isolated hypoplastic left heart syndrome
HUMAN GENETICS AND GENOMICS ADVANCES, 4(4).
TL;DR:
The findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of i HLHS, and identify a novel pathway involved in HLHS pathogenesis.
(via Semantic Scholar)
doi.org (publisher)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science; OpenAlex)
Source: Web Of Science
Added: October 16, 2023
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.