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

Ropers, H. H., & Wienker, T. F. (2015). Penetrance of pathogenic mutations in haploinsufficient genes for intellectual disability and related disorders. European Journal of Medical Genetics, 58(12), 715-718. doi:10.1016/j.ejmg.2015.10.007.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-BF33-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-BF34-F
Genre: Journal Article

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 Creators:
Ropers, H. Hilger1, 2, Author              
Wienker, Thomas F.3, Author              
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
2Institute for Human Genetics, University Medicine, Langenbeckstrasse 1, Building 601, 55131 Mainz, Germany, ou_persistent22              
3Clinical Genetics (Thomas F. Wienker), Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385696              

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Free keywords: Databases, Genetic Developmental Disabilities/*genetics *Genetic Association Studies *Haploinsufficiency Humans *Mutation *Penetrance Web Browser
 Abstract: 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 (http://exac.broadinstitute.org), 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 (http://evs.gs.washington.edu/EVS/). 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.

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Language(s): eng - English
 Dates: 2015-10-242015-12
 Publication Status: Published in print
 Pages: 4
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ejmg.2015.10.007
ISSN: 1878-0849 (Electronic)1769-7212 (Print)
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Title: European Journal of Medical Genetics
  Other : Eur. J. Med. Gen.
Source Genre: Journal
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Publ. Info: Amsterdam : Elsevier Masson SAS
Pages: - Volume / Issue: 58 (12) Sequence Number: - Start / End Page: 715 - 718 Identifier: ISSN: 1769-7212
CoNE: https://pure.mpg.de/cone/journals/resource/954925379964