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

Elizabeth E Blue1,2, Janson J White3, Michael K Dush4

  • 1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.

HGG Advances
|September 4, 2023
PubMed

Insights

Isolated hypoplastic left heart syndrome (iHLHS) is rarely caused by single gene mutations. New research implicates variations in the CAPN2 gene in increasing the risk for this severe congenital heart defect.

Area of Science:

  • Cardiovascular Genetics
  • Developmental Biology
  • Congenital Heart Disease Research

Background:

  • Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) comprising 4-8% of all CHDs and causing 25% of CHD deaths.
  • Isolated HLHS (iHLHS) occurs in 70% of families, often without a clear genetic cause.
  • The genetic basis of iHLHS remains largely unknown despite significant research efforts.

Purpose of the Study:

  • To investigate the genetic underpinnings of isolated hypoplastic left heart syndrome (iHLHS).
  • To identify genetic variants associated with iHLHS risk.
  • To explore the role of identified genes in cardiac development.

Main Methods:

  • Exome sequencing was performed on 331 families with iHLHS from four independent cohorts.
  • Mendelian-model-based analysis and gene-based association testing were employed.
  • Functional validation studies were conducted in a Xenopus laevis vertebrate animal model.

Main Results:

  • Mendelian analysis revealed that iHLHS is not typically caused by single, large-effect alleles in known CHD genes.
  • Gene-based association testing identified an increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10⁻⁵).
  • Functional studies confirmed CAPN2's essential role in cardiac ventricle morphogenesis, with identified human variants acting as hypomorphic alleles.

Conclusions:

  • iHLHS is generally not a Mendelian condition.
  • CAPN2 variants are associated with an increased risk of iHLHS.
  • This study identifies a novel pathway involved in HLHS pathogenesis, highlighting the role of calpain in cardiac development.

Keywords:
Xenopusassociationcongenital heart defectdevelopmentexome sequencingfrogoligogenic

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