Po-04-125 spectrum, prevalence, and implications of incidental variant findings in cardiac disease-associated genes during preventative genetic testing

Classically, genetic testing has been reserved for individuals with a reasonable pre-test probability of disease. However, the use of commercial preventative genetic testing (PGT) to identify asymptomatic individuals at risk for various heritable disorders, most commonly those linked to cancer and cardiovascular disease, has increased significantly. To describe our experience regarding incidentally discovered pathogenic (P)/likely pathogenic (LP) variants in otherwise healthy patients undergoing PGT. An institutionally developed natural language processing algorithm was used to identify all patients who underwent PGT at Mayo Clinic. The clinical characteristics, demographics, rationale for PGT, family history, variant adjudication, and cardiac work-up results for those whose PGT result included a channelopathy- or cardiomyopathy-inclusive cardiac panel were abstracted from the electronic medical record. Overall, 666/1269 (52%) patients that underwent PGT had ACMG reportable genetic heart disease (GHD)-susceptibility genes included. Of those, 10/666 (2%, 3 females, and mean age at time of PGT 59±10 years) had an incidentally discovered P/LP variant in one of 7 Clinical Genome Resource-adjudicated strong/definitive evidence GHD-susceptibility genes (DSG2, DSP, FLNC, KCNE1, MYBPC3 [n=2], MYH7 [n=2], and PKP2). Comprehensive cardiac work-up was recommended for all P/LP variant-positive patients and pursued in 8 (80%). Whereas no evidence of an underlying cardiac channelopathy or genetic cardiomyopathy was identified, 1 patient did have a positive test for ischemia. Interestingly, none of the patients with an incidentally discovered P/LP variant in a strong evidence cardiomyopathy (n=8) or channelopathy (n=1) gene that underwent further clinical evaluation had overt electrocardiographic or imaging evidence of an associated disease phenotype. Furthermore, family history was reviewed, and no patients had a family history consistent with the GHD in question. Overall, in 10 patients who had an incidental P/LP variant upon PGT, there was limited evidence of an underlying genetic channelopathy or cardiomyopathy phenotype suggesting the penetrance/expressivity of these incidentally discovered variants is exceedingly low. Patients considering preventative genetic testing should be counselled on the rate of incidentally identified findings as well as the potential clinical and psychosocial ramifications.