Abstract 15534: Interpreting HCM Genetic Testing in the Age of the Exome
Introduction: Recent publications from the 1000 genomes project (1kG) and the NHLBI Exome Sequencing project (ESP) have exposed the presence of rare (minor allele frequency (MAF) < 0.5%) non-synonymous variants (rNSVs) in HCM-associated genes that can complicate genetic test interpretation. In order to improve genetic test interpretation, the phenotype of patients with an established HCM diagnosis hosting rNSVs was assessed.
Method: The frequency of rNSVs in HCM-associated genes (MYH7, MYBPC3, MYL2, MYL3, TPM1, TNNT2, TNNI3, TNNC1, ACTC) were compared between 2178 cases (1053 Mayo Clinic, 1125 Transgenomic) and 8022 controls (1kG, ESP, “in-house”). Age at diagnosis, mean left ventricular wall thickness (MLVWT), a history of hypertension (HTN), and family history (FHx) were assessed in 1053 cases.
Results: While 395 distinct, case-exclusive NSVs were identified, 64 rNSVs were present in both cases and controls. Ten of these 64 rNSVs had a MAF<0.04% and were statistically overrepresented in cases and the patients hosting one of these 10 rNSVs were younger at diagnosis (p<0.001) with larger MLVWT (p=0.001), stronger FHx (p<0.001), and were less likely to have HTN (p=0.007) compared to patients with a negative genetic test. In contrast, those cases hosting one of the remaining 54 rNSVs (15 had MAF between 0.04-0.5% and 39 rNSVs with a MAF<0.04% but not overrepresented in cases) were indistinguishable from those with a negative genetic test. Interestingly, cases hosting multiple rNSVs displayed a phenotype similar to those patients with multiple mutations HCM.
Conclusions: Despite their presence in the publicly available exomes, rNSVs with a MAF < 0.04% and statistically overrepresented among patients with HCM may be possible HCM-associated mutations. In contrast, the control compendium of rNSVs that are not overrepresented in HCM cases are less likely to be causal mutations regardless of their MAF. However, cases hosting multiple rNSVs, regardless of their individual presence in controls, exhibit a severe phenotype and raise the possibility of digenic/polygenic-mediated disease.
- © 2013 by American Heart Association, Inc.