TY - JOUR

T1 - Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease

AU - Izarzugaza, Jose M.G.

AU - Ellesøe, Sabrina G

AU - Doganli, Canan

AU - Ehlers, Natasja Spring

AU - Dalgaard, Marlene D.

AU - Audain, Enrique

AU - Dombrowsky, Gregor

AU - Banasik, Karina

AU - Sifrim, Alejandro

AU - Wilsdon, Anna

AU - Thienpont, Bernard

AU - Breckpot, Jeroen

AU - Gewillig, Marc

AU - Brook, J David

AU - Hitz, Marc-Phillip

AU - Larsen, Lars A

AU - Brunak, Søren

AU - Competence Network for Congenital Heart Defects, Germany

PY - 2020

Y1 - 2020

N2 - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.

AB - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.

U2 - 10.1186/s13073-020-00772-z

DO - 10.1186/s13073-020-00772-z

M3 - Journal article

C2 - 32859249

VL - 12

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

IS - 1

M1 - 76

ER -