PROJECT SUMMARY This core is central for all experiments in this program project and capitalizes on the Pakistan Genomic Resource (PGR) that has established the largest biobank of “Human Knockouts”. Specifically, PGR has leveraged high levels of consanguinity in Pakistan and has conducted whole-exome and whole-genome sequencing studies in 80,000 participants and has already identified complete KOs for >5000 genes and heterozygous KOs for >18,000 genes. PGR has also found rare homozygotes for many missense variants, many of which have now been characterized to be loss of function (LoF) or gain of function (GoF). Moreover, PGR has also recruited > 45,000 cases with myocardial infarction, > 20,000 cases with echo-confirmed heart failure, > 6,000 cases with imaging confirmed stroke – all of these participants have undergone genotyping for GWAS and whole-exome sequencing studies. Services that will be provided by the core will include: (i) for high priority genes across the four projects, deep phenotyping of KOs / mutant probands and their consanguineous family members. Such phenotyping studies will include: detailed clinical exams, electrocardiograms (ECGs) and echocardiograms, assessment of any rhythm disorders through Biotel patch heart monitors, exercise stress test, and detailed biochemical exams; (ii) analyses of large-scale genomic data in relation to cardiovascular traits and outcomes (i.e., myocardial infarction, stroke, heart failure, ECG traits and other risk factors) recorded in PGR, UKBiobank and other population-based resources in up to 1 million participants.