Penetrance of pathogenic mutations in haploinsufficient genes for intellectual disability and related disorders

Eur J Med Genet. 2015 Dec;58(12):715-8. doi: 10.1016/j.ejmg.2015.10.007. Epub 2015 Oct 24.


De novo loss of function (LOF) mutations in the ASXL3 gene cause Bainbridge-Ropers syndrome, a severe form of intellectual disability (ID) and developmental delay, but there is evidence that they also occur in healthy individuals. This has prompted us to look for non-pathogenic LOF variants in other ID genes. Heterozygous LOF mutations in ASXL1, a paralog of ASXL3, are known to cause Bohring-Opitz syndrome (BOS), and benign LOF mutations in this gene have not been published to date. Therefore, we were surprised to find 56 ASXL1 LOF variants in the ExAC database (, comprising exomes from 60,706 individuals who had been selected to exclude severe genetic childhood disorders. 4 of these variants have been described as disease-causing in patients with BOS, which rules out the possibility that pathogenic and clinically neutral LOF variants in this gene are functionally distinct. Apparently benign LOF variants were also detected in several other genes for ID and related disorders, including CDH15, KATNAL2, DEPDC5, ARID1B and AUTS2, both in the ExAC database and in the 6,500 exomes of the Exome Variant Server ( These observations argue for low penetrance of LOF mutations in ASXL1 and other genes for ID and related disorders, which could have far-reaching implications for genetic counseling and research.

Publication types

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

MeSH terms

  • Databases, Genetic
  • Developmental Disabilities / genetics*
  • Genetic Association Studies*
  • Haploinsufficiency*
  • Humans
  • Mutation*
  • Penetrance*
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