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Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease

Jose M G Izarzugaza1, Sabrina G Ellesøe2, Canan Doganli3

  • 1Department of Health Technology, Technical University of Denmark, Kemitorvet, DK-2800, Kgs. Lyngby, Denmark.

Genome Medicine
|August 30, 2020
PubMed

Insights

This study reveals abnormal calcium signaling as a new mechanism in congenital heart disease (CHD). Genetic analysis in families with CHD highlights the complex genetic factors contributing to this common birth defect.

Area of Science:

  • Genetics
  • Cardiology
  • Systems Biology

Background:

  • Congenital heart disease (CHD) affects nearly 1% of newborns and is multifactorial.
  • Genetic factors significantly contribute to CHD etiology, leading to familial segregation.
  • Identifying pathophysiological mechanisms in CHD-affected families is crucial.

Purpose of the Study:

  • To identify pathophysiological mechanisms in families with segregating congenital heart disease.
  • To investigate the role of rare genetic variants in CHD development.
  • To explore the genetic architecture underlying CHD.

Main Methods:

  • Whole exome sequencing in 90 participants from 32 Danish families with recurrent CHD.
  • Systems biology approach to analyze rare variant accumulation and developmental mechanisms.
  • Replication in an independent cohort (714 CHD cases, 4922 controls) and functional studies in zebrafish.

Main Results:

  • Identified 1785 genes with shared rare alleles in affected family members; 218 mutated in multiple families.
  • Discovered a functional cluster enriched for proteins involved in calcium signaling.
  • Confirmed increased mutation burden in calcium-signaling genes in CHD patients and demonstrated roles for ITPR1, PLCB2, and ADCY2 in zebrafish cardiac development.

Conclusions:

  • Abnormal calcium signaling is a novel pathophysiological mechanism in human CHD.
  • The study confirms the complex genetic architecture underlying congenital heart disease.
  • Findings suggest a combinatorial effect of genetic variants in calcium signaling pathways in CHD etiology.
Abstract

Keywords:
Calcium signalingCongenital heart diseaseDevelopmental biologyGeneticsSystems biologyWhole exome sequencing

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