Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting

Am J Hum Genet. 2019 Feb 7;104(2):275-286. doi: 10.1016/j.ajhg.2018.12.015. Epub 2019 Jan 18.


More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.

Keywords: SNP-chip; biobank; genetic; genotyping; pathogenicity; penetrance; rare variant; variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Databases, Genetic
  • Developmental Disabilities / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Disease / genetics*
  • Female
  • Genetics, Population*
  • Heterozygote
  • Humans
  • Male
  • Mutation / genetics*
  • Penetrance*
  • Reproducibility of Results
  • Sunburn / genetics
  • Uncertainty
  • United Kingdom
  • Xeroderma Pigmentosum / genetics