Polygenic modifiers impact penetrance and expressivity in telomere biology disorders.

ABSTRACT: BACKGROUNDTelomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs.METHODSWe constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank.RESULTSIndividuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores p

SUBMITTER: Poeschla M 

PROVIDER: S-EPMC12352891 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature