Comprehensive Comparison of a Genotype-Forward vs. Phenotype-Forward Approach for Monogenic Cardiovascular Diseases in the UK Biobank Cohort

Background Monogenic cardiovascular diseases (MCVD) remain substantially under-diagnosed, and thus interest is shifting from a phenotype-forward approach towards a genotype-first strategy that applies to population-wide genomic screening. We evaluated the prevalence of pathogenic and predicted pathogenic MCVD variants and assessed disease expression in the population-based UK Biobank (UKB) cohort to determine whether yield is greater in phenotype- versus genotype-forward approach. Methods Pathogenic and likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) predicted to be pathogenic (pp-VUS) in 47 MCVD genes were assessed. In the genotype-forward approach, UKB participants with P/LPs or pp-VUS were assessed for symptoms of disease using electronic health record (EHR) interrogation, emulating a clinical approach to population-based screening. In the phenotype-forward approach, participants with stricter EHR-based evidence of disease expression were identified (emulating current clinical care) and the presence of P/LPs and pp-VUS was determined. Results Following QC, 467,850 participants were included. Overall, 1 in 125 participants in UKB carry an MCVD P/LP. In the genotype-forward approach, 3,709 (0.79%) participants carried an MCVD P/LP and 42.1% of these had symptoms of the associated MCVD; another 29,269 (6.3%) carried a pp-VUS with 21.5% of these having symptoms of disease. In the phenotype-forward approach, 62,488 (13.4%) expressed an MCVD using strict evidence of disease expression and of these individuals 1% carried an associated P/LP variant and 2.4% carried an associated pp-VUS. Conclusion We show here that a genotype-forward approach leads to a 2.5 times higher diagnostic yield (3.6 times higher when considering pp-VUS) compared with the phenotype-forward approach, which missed 936 P/LP carriers with disease symptoms. While cost, access and ethics need to be considered, these results support expanded population-based genetic screening to improve diagnosis of potentially treatable MCVD.