Polygenic scores as modifiers in Mendelian diseases.

Area of Science:

• Genetics
• Genomics
• Medical Genetics

Background:

• Mendelian diseases arise from rare, high-impact genetic variants.
• Phenotypic variation (variable expressivity, incomplete penetrance) within Mendelian diseases suggests complex genetic underpinnings.
• Common genetic variants, individually small in effect, can collectively influence phenotypes via polygenic scores (PGS).

Purpose of the Study:

• To review existing data on the phenotypic modification of Mendelian diseases by polygenic scores.
• To explore the role of common genetic variants in modulating the expression of rare genetic disorders.

Main Methods:

• Literature review of studies investigating polygenic score modification in Mendelian diseases.
• Synthesis of evidence demonstrating the impact of common variant backgrounds on rare disease phenotypes.

Main Results:

• Polygenic scores have been shown to modify penetrance and expressivity in carriers of rare pathogenic variants across diverse Mendelian conditions.
• The influence of common genetic variants on rare disease phenotypes appears to be a widespread phenomenon.

Conclusions:

• The genetic architecture of Mendelian diseases is more complex than simple rare variant effects, with common variants playing a significant modifying role.
• Understanding the interplay between common and rare variants is crucial for a comprehensive view of Mendelian disease genetics.
• Future research with increased data and advanced methods will refine our understanding of this complex genetic architecture.