Phenotypic expression of rare progressive cardiac conduction disease variants in the general population

Familial progressive cardiac conduction disease (PCCD) is a heritable condition leading to conduction defects that may require pacemaker implantation. The penetrance of rare PCCD variants in general populations and relationship with electrocardiogram (ECG) trait polygenic risk scores (PRS) is unknown. We investigated the prevalence and phenotypic expression of rare variants linked with PCCD in a population cohort and to establish whether ECG-trait PRSs improve risk prediction.

Carriers of known rare pathogenic/likely pathogenic (P/LP) PCCD variants, and variants of uncertain significance (VUS) were identified in 469 511 UK Biobank participants. Primary (any conduction disease) and secondary (high-grade AV block and pacemaker implantation) outcomes were evaluated in lifetime-risk Cox proportional hazard models including rare variant status, sex, and age. Additional models including PR and QRS PRSs were tested. There were 25 P/LP carriers (5 genes) and 3174 VUS carriers (4 genes). Conduction disease was more prevalent in P/LP individuals compared with non-carriers (28% vs. 5.3%, P < 0.001) with a hazard ratio (HR) of 6.60 (95% CI = 3.14–13.8) over 6.5 million person-years of follow-up and C-index 0.602 (0.599–0.605). This was driven by AV block (HR 23.2 [8.7–61.8]) and pacemaker implantation (HR 13.4 [6.01–29.8]). All individuals were aged >50 at diagnosis. Combined with P/LP status, PR-PRS and QRS-PRS improved model performance (C-index 0.618 [0.615–0.622]).

In a population-based cohort, PCCD P/LP variant carriers were at greater risk of conduction disease. Including PRSs for the PR and QRS improved risk prediction, supporting the combination of rare and common variants in risk assessment.