Advancing precision medicine in heritable cardiac diseases: genetic insights from the understudied Middle Eastern population (360G-Wellcome-309669_Z_24_Z)

Cardiovascular diseases (CVDs) represent the leading cause of mortality worldwide with >75% of CVD deaths occurring in low- and middle-income countries (LMICs). Genetic cardiomyopathies (CMs) are important causes of CVD and represent major causes of death and heart transplantation in young individuals. The genetic architecture of CM is complex with rare disease- causing variants identified in <40% of patients. Most of our knowledge on its genetic aetiology is derived from European-ancestral populations while patients from LMICs, including Middle East and North Africa (MENA) are severely underrepresented. Therefore, there are two motivations to study MENA: a) a moral need to address health inequalities and b) an opportunity to discover novel patterns of genetic variation by studying a consanguineous population. To achieve this, I will perform three work packages in an Egyptian population, the largest in MENA. These are: 1) Characterise and validate Egyptian-specific variants of novel- and understudied variant classes, 2) Discover novel recessive/de novogenes/variants in genetically unexplained patients, 3) Investigate the contribution of common variation to CM risk and severity. This study will enhance our knowledge of the genetic aetiology of CM and identify needs of underserved MENA patients so that they can benefit from precision medicine and emerging therapies.