Key result
Pathogenic PCCD variant carriers show ~560% higher conduction disease risk than non-carriers.
Why the study?
The penetrance of rare progressive cardiac conduction disease variants in general populations and their relationship with ECG trait polygenic risk scores were unknown.
Does the presence of rare pathogenic/likely pathogenic PCCD variants and ECG-trait polygenic risk scores increase the risk of conduction disease in the general population?
Cohort (n=469,511)
Does the presence of rare pathogenic/likely pathogenic PCCD variants and ECG-trait polygenic risk scores increase the risk of conduction disease in the general population?
In a population cohort, carriers of rare pathogenic progressive cardiac conduction disease variants have a significantly higher risk of conduction disease, and combining this with polygenic risk scores improves risk prediction.
May support variant-based risk stratification for conduction disease; extends associations to large cohorts but leaves open clinical utility.
AIMS: 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. METHODS AND RESULTS: 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]). CONCLUSION: 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.
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Shah et al. (2025) conducted a cohort in Progressive cardiac conduction disease (PCCD) (n=469,511). Pathogenic/likely pathogenic (P/LP) PCCD variants vs. Non-carriers was evaluated on Any conduction disease (HR 6.60, 95% CI 3.14-13.8, p=< 0.001). Carriers of pathogenic/likely pathogenic PCCD variants had a higher risk of conduction disease than non-carriers (28% vs 5.3%; HR 6.60; 95% CI 3.14-13.8; P<0.001).
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