Polygenic modifiers of expressivity in telomere biology disorders

Variable expressivity, where individuals carrying identical genetic variants display diverse phenotypes, presents an important challenge in clinical genetics. This is exemplified by the telomere biology disorders (TBDs), which exhibit tremendous clinical heterogeneity despite their presumed monogenic nature, even among individuals harboring the same pathogenic variant. Here, we studied cohorts of patients with TBDs and population biobanks to demonstrate that common genome-wide polymorphisms associated with variation in telomere length in the general population combine with large-effect causal variants to significantly impact TBD expressivity. We go on to show that polygenic variation can contribute to expressivity within a single family with a shared large-effect causal variant, and that common and rare variation converge on a shared set of genes implicated in telomere maintenance. By elucidating the role of common genetic variation in rare disease expressivity in TBDs, these results provide a framework for understanding phenotypic variability in other presumed monogenic disorders.