Resumen de Identifiaction of genetic modifiers of penetrance in human inherited disease
Understanding the molecular basis of human inherited disease is a challenging task due to the complexity of mapping the genotype to the phenotype. The study of diseases running in families has shown that the inheritance of certain variants confers disease susceptibility. However, not all carriers of such pathogenic variants express the clinical symptoms, a phenomenon known as reduced penetrance. This thesis has investigated a potential mechanism of genetic modification for the penetrance of a missense BMPR2 mutation in heritable pulmonary arterial hypertension (HPAH) by applying genetic linkage analysis to a large multiplex family. We have identified a candidate region for a modifier in the distal promoter region of the FIGN gene supported by lung-specific regulatory activity and risk factors associated with blood pressure. Taken together, these results suggest that common regulatory variants may have an important role in determining the penetrance of pathogenic coding variants. This thesis also provides a resource to integrate genome-wide position-specific scores routinely used in variant prioritization.
