Polygenic scores as modifiers in Mendelian diseases.

Mendelian diseases are caused by rare pathogenic variants with large effects. However, phenotypes are often different between individuals carrying the same variant ("variable expressivity"), or even absent in some carriers ("incomplete penetrance"), suggesting that the genetic architecture of Mendelian diseases is more complex than previously thought. Common genetic variants are a potential modifier of observed phenotypes. Individual common variants usually have small effects, but in aggregate their effects can be substantial and be quantified as a polygenic score (PGS). The present review summarises available data on how PGS modify phenotypes in Mendelian diseases. We show that modifying effects of PGS on penetrance and expressivity have been observed in carriers of rare pathogenic variants across a broad range of conditions. This suggests that in Mendelian diseases, a modifying effect of the common variant background on penetrance and expressivity might be the rule rather than the exception. We anticipate that increasing data availability and methodological advances will improve our understanding of the genetic architecture of Mendelian diseases, including the joint consideration of both common and rare variants.

© 2026 the author(s), published by De Gruyter.

PMID: 42416882