MD/PhD Candidate University of British Columbia Vancouver, British Columbia, Canada
Background: Hypertrophic cardiomyopathy (HCM) is a common inherited disease and a leading cause of sudden cardiac arrest in young adults and athletes. While genetic testing has advanced rapidly in the past decade, the yield of genetic testing remains low. The Clinical Genome Resource (ClinGen) initiative has become a leading resource for defining the clinical relevance of genetic variants, with expert groups focusing on evaluating the strength of evidence for each HCM implicated gene. With the rise of large biobanks and population databases, genetic discovery has been significantly advanced. However, whether these databases can be used to validate gene-disease associations curated by ClinGen and provide evidence for novel gene-disease associations remains unclear.
METHODS AND RESULTS: We utilized a recently established phenome-wide association study database which tested the association of rare coding variants with multiple phenotypes in 748,879 individuals across three large biobanks (All of Us, UK biobank, Mass General Brigham biobank), 155,236 of which are of non-European ancestry. We tested the association of each gene in the HCM ClinGen panel with HCM, stratified by the gene’s ClinGen evidence classification (definitive, moderate, limited, disputed, no known disease relationship). The analysis was limited to rare variants (minor allele frequency < 0.1%) and the one phenocode available for HCM (“other hypertrophic cardiomyopathy”), with a P value < 0.05 considered statistically significant. Of the 12 genes with definitive evidence for HCM (e.g., MYBPC3, MYH7, TNNT2, ALPK3), 8 (67%) demonstrated significant association with HCM on a population level, further supporting the validity of these genes in HCM panels. The four definitive genes (TPM1, FHOD3, MYL2, and TNNC1) that did not reach significance had positive associations with HCM, and are considered ultrarare in HCM, suggesting the study was likely underpowered for ultrarare variants in those genes. Of those, TPM1 was nearly significant (P=0.07). No genes deemed to have moderate (n=3) or limited (n=9) evidence were significantly associated with HCM. Interestingly, within the 13 disputed genes, two (15%) genes (MYOM1, DSP) reached statistical significance but had notably lower effect sizes and greater P values compared to definitive genes.
Conclusion: Altogether, we show that large biobanks and population databases generally recapitulate established gene-disease associations for HCM and support the ClinGen group's gene curations. Utilization of publicly accessible databases represents an important tool for assessing gene validity in monogenic cardiac disorders with an established phenotype. This approach may also be useful in validating novel candidate HCM genes across populations, particularly those of diverse genetic ancestry.
