Abstract 4363815: Identifiable Penetrance in Patients with Secondary Findings Associated with Mendelian Cardiovascular Disease

Abstract

Introduction: Pathogenic and likely pathogenic (P/LP) variants in 52 cardiovascular genes identified as secondary findings (SF) in clinical sequencing are considered reportable by the ACMG. These are defined due to a high likelihood of disease, and early identification may have important implications. The risk of disease development and appropriate long-term follow-up remain uncertain. Methods: Patients with SF identified on exome, genome or panel testing performed for non-cardiac indications were referred to a specialist cardiovascular genetics center. All variants were reclassified using ACMG criteria. Clinical evaluation included condition-specific investigations and use of contemporaneous diagnostic criteria to determine, with penetrance considered as expression of a concordant phenotype. Management was based on clinically defined disease at the time of evaluation. Cascade testing in further family members (FM) was performed as indicated. Results: Clinical evaluation was performed in 135 patients (mean age 16.2 years; 47% male), including testing probands (n=74), FM as part of initial testing strategy (n=36) and cascade testing in other FM (n=25). Of the 153 variants identified in 25 cardiovascular genes, 88 patients had a P/LP variant. P/LP variants in KCNQ1 (19), SCN5A (14), MYBPC3 (12), and TTN (9) were most prevalent. In 17 patients referred, the gene was not considered reportable. Penetrance was identified in 26 patients (9 probands, 17 FM) with P/LP variants, and 2 with biallelic variants of unknown significance. The phenotypes were channelopathy (16), cardiomyopathy (11) and aortopathy (1). Those with a phenotype were older (22.1 vs 14.8 years; p<0.05) and more likely to have a positive family history (15/28 vs 25/107; p<0.001). In 62 (71%) with P/LP variants, no phenotype was identified. Cardioverter-defibrillators were implanted in 3, and 26 were started on beta-blockers. One patient underwent cardiac sympathetic denervation. Follow-up was recommended for 110 (81%). Conclusions: Penetrant cardiac disease is identifiable in an important minority of patients with SF, associated with age and family history, supporting the need for detailed evaluation and longitudinal management of all patients with incidentally discovered variants that cause monogenic heart disease. Notably patients with non-reportable findings were also referred for evaluation. The longer-term impact of non-penetrant variants and follow-up requires ongoing evaluation.