Subphenotype-based characterisation of signalling pathways in congenital heart defects (CHD)

Congenital heart defects (CHDs) are the most common (1 - 2 %) birth defects amongst live newborns. Despite more than 200 genes having been associated with the development of CHD, the molecular basis remains partially unclear, and only a minority of patients can be assigned to an underlying genetic variant. The identification and characterisation of novel genetic variants increases diagnostic yields, improves risk stratification and, thus, the overall clinical management of CHD patients. By analysis of an exome-based case-control study comprising of 3907 CHD-cases and 5157 population matched controls, this thesis focussed on enhancing the understanding of the genetic contribution to CHD in general and on revealing sub-phenotype specific differences.

Established CHD-genes were investigated with respect to deleterious variants that might account for the patient´s phenotype. Clustering based on phenotypic subtypes followed by GO-term enrichment revealed distinct genes and mechanisms underlying the different CHD subtypes.
Secondly, a permutation-based analysis of signalling pathways revealed 26 of the tested combinations to be significantly enriched. Molecular dynamics was utilised to determine the molecular mechanisms of variants localised in PTPN11 and PIK3CA.
The last part was focussed on NOTCH1, a gene that has been consistently determined to be one of the key contributors to CHD. Besides truncating variants, alterations in disulfide-bonds in NOTCH1 were significantly enriched. Functional analysis showed a complete impairment of the signalling capability for the tested nonsense variants and moderately reduced capabilities for missense variants.
In summary, this thesis provides novel insights into the genetic background, including specific CHD subgroups, which might offer novel surveillance and treatment strategies for CHD patients in the future.

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