Rare telomere biology disorder (TBD) pathogenic genetic variants do not always result in overt disease, and affected individuals exhibit considerable phenotypic variability — from relatively minor to severe. One hypothesis is that background genetic variation beyond the primary pathogenic variant contributes to this variety of outcomes. (A) Common variants associated with mean telomere length through a GWAS performed by Poeschla and colleagues can be used to generate polygenic scores (PGS) that represent telomere length predisposition. (B) They found that this score shifts the total genetic liability in individuals who also carry rare TBD pathogenic variants, influencing both the probability of developing TBD and disease severity. Individuals with a a high-risk PGS (short telomere predisposition; top) have increased risk of crossing a TBD liability threshold, often manifesting as early onset disease, while those with a low-risk PGS (long telomere predisposition; bottom) are less likely to manifest disease, despite carrying the same rare variant. Importantly, the genetic liability threshold for TBD is only relevant in the context a pathogenic variant, and there are some individuals to the left of the liability threshold who do not have severe disease, indicating the complex genetic architecture yet to be uncovered.