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

Izarzugaza, J.M.G., Ellesøe, S.G., Doganli, C., Ehlers, N.S., Dalgaard, M.D., Audain, E., Dombrowsky, G., Banasik, K., Sifrim, A., Wilsdon, A., Thienpont, B., Breckpot, J., Gewillig, M., Competence Network for Congenital Heart Defects, Germany, Brook, J.D., Hitz, M.P., Larsen, L.A., Brunak, S.
Genome Medicine   12: 76 (Journal)
Registered Authors
Doganli, Canan, Thienpont, Bernard
Calcium signaling, Congenital heart disease, Developmental biology, Genetics, Systems biology, Whole exome sequencing
MeSH Terms
  • Alleles
  • Animals
  • Calcium/metabolism*
  • Calcium Signaling*
  • Computational Biology/methods
  • Databases, Genetic
  • Denmark
  • Exome Sequencing
  • Female
  • Genetic Association Studies/methods
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/metabolism*
  • Humans
  • Male
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Registries
  • Systems Biology/methods*
  • Zebrafish
32859249 Full text @ Genome Med.
Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD.
We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model.
We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes.
The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes