Proband and family member disease penetrance in cardiac genetic secondary findings

Abstract

Abstract Background Broad genomic screening including whole exome sequencing (ES) is increasingly used in clinical care. Families may elect to receive pathogenic and likely pathogenic genetic variants in 30 genes associated with inherited cardiac disorders recommended as reportable by the ACMG, termed cardiac secondary findings (CSF). Most families (91%) opt to receive CSF for the proband, and 73% of parents opt to receive CSF for themselves1. Our initial experience of 33 patients with 22 different CSF identified a low diagnostic yield and high proportion of patients referred for evaluation with non-reportable findings, with only 4 CSF classified as P/LP (4/22; 18%). Three patients (9%) had concordant clinical findings but none met diagnostic criteria2. Purpose The purpose of this analysis was to evaluate the genetic and clinical findings in a secondary cohort. Methods All patients who presented to a joint familial cardiogenetic clinic were included. Identified CSF were categorized by 2015 ACMG criteria for variant classification. Clinical evaluation was performed using contemporaneous diagnostic criteria based on potential phenotypes associated with identified CSF. Variant classification and clinical findings were compared in the initial and secondary cohorts. The study was approved by the Institutional Review Board. Results Forty patients (20 male; age 19.5±15.9 years) from 20 families were evaluated with 19 different CSF. The variant consequence was missense (12), frameshift (6) and premature stop codon (1), and ACMG classification was pathogenic/likely pathogenic in 15/19 (79%) (p<0.01). Complete clinical evaluation was performed in 35 (88%) individuals and is ongoing in 5. Concordant findings were identified in 12/35 (34%) (p<0.04) including 5 adults and 7 children. CSF and associated phenotype included TTN – LV dilatation (1); KCNQ1 – LQTS (5); DSP – arrhythmogenic cardiomyopathy (ACM) (4); RYR2 – CPVT (1); SCN5A – 1st degree AV block (1). Two patients were symptomatic prior to diagnosis; a 16-year-old female with palpitations and ventricular ectopy considered benign (DSP), and a 41-year-old female with syncope and documented torsade de pointes experienced before cascade screening (KCNQ1). Three patients received defibrillators on primary (ACM) or secondary (LQTS) prevention indications and 2 received ILRs (ACM). Beta-blockers were prescribed for 5 with LQTS (3), CPVT (1) and KCNQ1 CSF but no phenotype (2). Avoidance of provocative medication was recommended for 11. Ten patients with pathogenic CSF (MYBPC3 (2), RYR2 (1), SCN5A (4), KCNH2 (3)) had no discernable phenotype. Conclusions In this secondary analysis there was a marked increase in the proportion of pathogenic/likely pathogenic CSF and associated clinical findings, including those necessitating significant management strategies. This data may help inform results disclosure and referral streams for patients with CSF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Mannion and Roberts Families Table 1