Project

Unraveling the molecular basis of congenital heart defects

Duration
01 January 2015 → 31 December 2020
Funding
Research Foundation - Flanders (FWO)
Promotor
Research disciplines
  • Medical and health sciences
    • Laboratory medicine
    • Medical systems biology
    • Laboratory medicine
    • Medical systems biology
    • Molecular and cell biology
    • Laboratory medicine
    • Medical systems biology
    • Molecular and cell biology
Keywords
congenital heart defects
 
Project description

Congenital heart defects (CHD) affect 1% of all life-born children and are a leading inborn cause of morbidity and mortality. CHD can be part of a syndromal constellation, but the vast majority occurs isolated and sporadically. Important progress has been made in the understanding of the molecular heterogeneity in syndromal CHD, while isolated forms remain largely unexplained. We hypothesize that mutations only present in cardiac progenitor cells (somatic mosaicism), de novo mutations, and mutations with highly reduced penetrance underlie sporadic CHD. Next-generation sequencing techniques enable analysis of the whole coding region of a patient’s genome (exome). We will perform targeted analysis of CHD genes in exome data of diseased cardiac tissue, harvested during surgery. In the absence of causal mutations, exome wide data comparison with exomes obtained from blood samples of both parents allows to detect de novo or somatic mutations in the child depending on whether or not the mutation is also present in the patient’s germline. In a final step, bioinformatic tools enable prioritization of candidate genes in an autosomal dominant model with reduced penetrance. Novel genes will be validated by genetic modification of zebrafish embryos, a prime model for the study of cardiovascular development and by the screening of larger patient cohorts. The results will provide novel molecular insights in CHD and, evenly important, will bode for the counselling of CHD families.