Genetic characterisation of selected probands/kindreds with congenital heart disease

Abstract

Congenital Heart Disease (CHD) is a rare multifactorial disease affecting around 1% of the population. CHD has a complex aetiology involving genetic, environmental, and maternal factors. The genetic factors driving CHD are also numerous, with syndromic, chromosomal, monogenic and polygenic factors implicated in its development. Within the past few decades, a minority of patients diagnosed with this disorder were known to survive until adulthood, hence research in this field is ever growing. This dissertation entitled "Genetic Characterisation of Selected Probands/Kindreds with Congenital Heart Disease” presents findings from genomic analysis of an adult proband with complex cyanotic CHD complicated by pulmonary hypertension and Eisenmenger syndrome. Trio whole exome sequencing was performed on the proband and unaffected parents followed by bioinformatic analysis to identify deleterious variants segregating using different disease models (dominant with reduced penetrance, recessive, de-novo) that could possibly explain the observed phenotype. Variant filtering and prioritisation was performed with reference to a large gene panel (n = 635 loci) derived from the literature having possible association with CHD. A de novo pathogenic missense variant in BMPR2 p.Arg491Trp rs137852746 was identified in the proband that was absent from an ethnically matched reference cohort. Molecular modelling was applied to evaluate physiochemical properties of this missense variant located in the kinase domain. This molecular modelling provided evidence for a deleterious effect of this variant on protein stability. Our findings identify a monogenic driver for pulmonary hypertension in the proband that holds significant implications for clinical practice. This locus has been previously associated with pulmonary hypertension and CHD. BMPR2 has been associated with microvascular and aortic endothelial cell development along with vascular development, whilst also being the primary gene associated to the development of PAH in humans.