Identifying novel genes that cause congenital heart disease

Complex genetic networks underlie the development of the heart. Variants in some of these genes can lead to congenital heart disease (CHD). Despite the hundreds of genes that have been identified as causing CHD in humans, they only account for a small proportion of individuals with CHD. We carried out whole exome sequencing in the largest cohort of individuals with CHD reported at the time of publication, and identified three novel genome wide significant syndromic CHD genes; CDK13, PRKD1 and CHD4. Individuals with mutations in CHD4 show neurodevelopmental disability, genital abnormalities and share some phenotypic overlap with other chromatinopathies. Mutations in PRKD1 also cause syndromic CHD, but identification of further affected individuals is required to determine if there is a consistent phenotype. Prkd1 mouse models do not have a high incidence of CHD, but this gene may be important in future work as it plays a role in cardiac hypertrophy. Individuals with mutations in CDK13 show a recognisable phenotype and the mouse model shows embryonic lethality and atrioventricular canal defects. The precise mechanism by which heterozygous mutations cause disease in humans remains unclear. The phenotypic and genotypic spectrum has been expanded by subsequent reports of individuals with mutations in CKD13. We also identify a role for inherited variants with reduced penetrance in individuals with non-syndromic CHD. This is significant, as the vast majority of individuals with CHD have non-syndromic CHD. It is an important step in understanding the potential oligogenic pathogenesis of the majority of CHD. Ultimately we aim to increase our knowledge of the genes and networks that underlie CHD, to improve diagnostic yield in individuals affected with CHD. I was able to feedback pathogenic mutations in CHD genes to participants in this study locally. Following this unbiased approach of non-targeted testing in a cohort with multiple types of CHD, will improve our knowledge of