Can variants of genes associated with familial heart block predict conduction disease in the general population? A UK Biobank study.

Abstract Background Progressive familial heart block is a genetic disease that can present with worsening cardiac conduction disease (CCD) and risk of life-threatening bradycardia. The prevalence, penetrance, and expressivity of known rare pathogenic/likely pathogenic variants (P/LP) in the general population is unclear. In addition, the role of common genetic variation in this phenotypic expression is unknown. Understanding this is essential for patient management in clinic. Purpose 1). To investigate the prevalence of variants linked with early-onset CCD and phenotypic expression in a large biobank. 2). To investigate whether a PR interval polygenic risk score (PRS) improves risk prediction. Methods Early-onset conduction disease P/LP or variants of uncertain significance (VUS) were identified from ClinVar, genetic testing reports at a teaching hospital (6 variants), and the literature, mapping to 22 genes. From the full UK Biobank prospective cohort, 469,511 participants passed genetic quality control and were assigned to P/LP, VUS, or genotype negative (G-) groups, using whole exome sequencing analysed with bcftools. A PR-PRS was constructed using weights from a published meta-analysis excluding UKB data. The primary outcome was CCD (atrioventricular (AV) block, bundle branch block, pacemaker or ICD implantation) and secondary outcomes were high-grade AV block or pacemaker insertion, compared with lifetime risk Cox proportional hazards controlled for sex and age as a timescale. Results 55% of participants were female, 95% had European ancestry, and average age at censor was 71 years. There were 25 P/LP carriers, and 8,862 with a VUS, in 6 genes (MYH7, SCN5A, TNNI3K, TRPM4, TTN, and LMNA). Major demographic factors were the same between groups. CCD was significantly more prevalent in P/LP individuals (28% vs 5.8% in VUS vs 5.5% in G-; p<0.001) with a hazard ratio of HR 6.47 [95% CI=3.09-13.6] vs G-. This was driven by AV block and pacemaker implantation (HR 23.2 [95% CI=8.69-61.8] and 13.4 [95% CI=6.01-29.8], respectively). Results were similar in an unrelated subset and controlling for ischaemic heart disease and heart failure. The 7 P/LP individuals with conduction disease were mostly linked to a single LMNA variant (4 out of 6 carriers with penetrant disease). In the full cohort, the PR-PRS was predictive of CCD (HR=1.07 [95% CI=1.06-1.08]), AV block (HR=1.09 [95% CI=1.06-1.13]), and pacemaker implantation (HR=1.04 [95% CI=1.02-1.06]). When combined with P/LP status, both PR-PRS (HR=1.07 [95% CI=1.06-1.08]) and P/LP (HR=6.42 [95% CI=3.06-13.5]) were independent predictors of CCD. Conclusion(s) Rare variant carrier status predicts a 6.5-fold increased lifetime risk of CCD, a 23-fold increased risk of AV block and 13-fold risk for pacemaker requirement. However, phenotypic expression for some variants is highly variable. A PR-PRS captures risk independent of P/LP variants and warrants further investigation with updated PRS construction methods.