000162048 001__ 162048
000162048 005__ 20251017144650.0
000162048 0247_ $$2doi$$a10.1093/europace/euaf103
000162048 0248_ $$2sideral$$a144630
000162048 037__ $$aART-2025-144630
000162048 041__ $$aeng
000162048 100__ $$aShah, Ravi A
000162048 245__ $$aPhenotypic expression of rare progressive cardiac conduction disease variants in the general population
000162048 260__ $$c2025
000162048 5060_ $$aAccess copy available to the general public$$fUnrestricted
000162048 5203_ $$aAims
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.
000162048 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/RYC2021-031413-I
000162048 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttps://creativecommons.org/licenses/by-nc/4.0/deed.es
000162048 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000162048 700__ $$0(orcid)0000-0003-4130-5866$$aRamírez, Julia$$uUniversidad de Zaragoza
000162048 700__ $$aKirkby, Claire
000162048 700__ $$aIves, Charlotte
000162048 700__ $$aLowe, Martin
000162048 700__ $$aMunroe, Patricia B
000162048 700__ $$aLambiase, Pier D
000162048 700__ $$aYoung, William J
000162048 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000162048 773__ $$g27, 6 (2025), 10$$pEuropace$$tEuropace$$x1099-5129
000162048 8564_ $$s440653$$uhttps://zaguan.unizar.es/record/162048/files/texto_completo.pdf$$yVersión publicada
000162048 8564_ $$s2196738$$uhttps://zaguan.unizar.es/record/162048/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000162048 909CO $$ooai:zaguan.unizar.es:162048$$particulos$$pdriver
000162048 951__ $$a2025-10-17-14:35:54
000162048 980__ $$aARTICLE