Although familial dilated cardiomyopathy (DCM) is often considered monogenic, clinical genetic testing finds pathogenic/likely pathogenic (P/LP) variants in only ~30% of probands. Cascade-testing of first-degree relatives is only recommended for P/LP carriers. TTN truncating variants explain 25% of cases but show variable penetrance. GWAS now demonstrate a substantial polygenic contribution to DCM. We hypothesised that adding polygenic risk score (PRS) analysis to standard genetic testing could improve diagnostic yield and inform decisions around cascade screening of relatives.
We studied 113 probands of European ancestry with clinically diagnosed DCM from the Australian Genomics Health Alliance (AGHA) Cardiovascular flagship. Clinical genetic testing identified P/LP variants in 34% of cases within known DCM genes. After comparing performance of multiple PRS methods in UK Biobank data, we used SBayesRC in this study. Using UK Biobank as a population reference, we identified the proportion in TTN P/LP carriers, other P/LP carriers and genotype-negative individuals (no P/LP identified) with a PRS in the top 10% of the reference PRS distribution.
We found 26% and 25% of DCM patients in the genotype-negative and TTN P/LP groups, respectively, had a PRS in the top decile, showing a statistically significant enrichment of high PRS in these groups, compared with only 11% in other P/LP group. Interestingly, there was complete depletion in bottom four deciles among the TTN P/LP group, providing evidence that polygenic contribution may play a larger role in these patients than in non-TTN carriers.
High PRS explains disease in a significant share of patients lacking identifiable monogenic variants and implies lower risk to relatives. It also appears to strongly contribute to disease development in TTN related DCM, potentially providing an explanation for variable penetrance. Therefore, incorporating PRS into routine genetic evaluation may improve diagnostic yield and guide counselling and risk management for patients and their family members.