Pathogenic variants in non-protein-coding sequences

Clin Genet. 2013 Nov;84(5):422-8. doi: 10.1111/cge.12272. Epub 2013 Sep 23.


There are approximately 3000 human protein-coding genes that have been linked with (near) monogenic disorders. This knowledge reflects the past and present focus on protein-coding genes as the main reservoir of pathogenic variation in the human genome. However, the 'Medical Genome' includes all the functional genomic elements for which genotypic variability is a source of pathogenic phenotypes. This short review focuses on examples of pathogenic variants in non-protein-coding gene regions. It is likely that the evolving methods of DNA sequencing and functional characterization of the genome will enhance our understanding of the contribution by all functional genomic elements in both Mendelian and complex phenotypes.

Keywords: enhancers; lncRNA; miRNA; non-coding sequences; pathogenic variants; promoters.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Craniofacial Abnormalities / diagnosis
  • Craniofacial Abnormalities / genetics*
  • DNA, Intergenic*
  • Enhancer Elements, Genetic
  • Genome, Human*
  • Humans
  • Limb Deformities, Congenital / diagnosis
  • Limb Deformities, Congenital / genetics*
  • MicroRNAs
  • Open Reading Frames
  • Promoter Regions, Genetic
  • Pseudogenes
  • RNA, Long Noncoding
  • Sequence Analysis, DNA
  • Spinocerebellar Degenerations / diagnosis
  • Spinocerebellar Degenerations / genetics*


  • DNA, Intergenic
  • MicroRNAs
  • RNA, Long Noncoding