Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population

Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant var-iants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from 200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from 500,000 individ-uals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelli-gence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.

Automated summary

This study investigated the phenotypic effect of rare, potentially deleterious variants in genes associated with monogenic developmental disorders (DDs) in a large population cohort. The findings suggest that individuals with these variants have mild DD-related phenotypes and significant socioeconomic disadvantages in the general adult population.