De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability
Stevens, Servi J.C.; van der Schoot, Vyne; Leduc, Magalie S.; Rinne, Tuula; Lalani, Seema R.; Weiss, Marjan M.; van Hagen, Johanna M.; Lachmeijer, Augusta M.A.; Stockler-Ipsiroglu, Sylvia G.; Lehman, Anna; Brunner, Han G.; CAUSES Study
(2018) Human Mutation, volume 39, issue 7, pp. 1014 - 1023
(Article)
Abstract
The role of disturbed chromatin remodeling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the “SET nuclear proto-oncogene” (SET), encoding a component of the
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“inhibitor of histone acetyltransferases” (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene. Additionally, an affected mother and child were detected who carried a frameshift variant in SET. Four patients were found in literature. The de novo mutations in patients affected all four known SET mRNA transcripts. LoF mutations in SET are exceedingly rare in the normal population and, if present, affect only one transcript. The pivotal role of SET in neurogenesis is evident from in vitro and animal models. SET interacts with numerous proteins involved in histone modification, including proteins encoded by known autosomal dominant ID genes, that is, EP300, CREBBP, SETBP1, KMT2A, RAC1, and CTCF. Our study identifies SET as a new component of epigenetic regulatory modules underlying human cognitive disorders, and as a first member of the Nucleosome Assembly Protein (NAP) family implicated in ID.
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Keywords: chromatin remodeling, de novo mutation, exome sequencing, intellectual disability, SET nuclear proto-oncogene, Genetics, Genetics(clinical)
ISSN: 1059-7794
Publisher: Wiley-Liss Inc.
Note: Funding Information: We thank Kees van Roozendaal and Rolph Pfundt for helpful discussions. We thank Kris Roberts, Rachel Coe, Liza Mak, and Michelle Zhou for supporting the CAUSES Study. The bioinformatics pipeline used for analysis of patient 1 data was based on that developed in the laboratory of Wyeth Wasserman, with intellectual contributions from Dave Arenillas, Phillip Richmond, Casper Shyr, Alison Matthews, and Maja Tarailo-Graovac. The CAUSES study is funded by the Mining for Miracles (British Columbia Children's Hospital Foundation) and Genome British Columbia, with support from the British Columbia Provincial Health Services Authority and British Columbia Women's Hospital. We thank the patients and families for their participation in this study. The Department of Molecular and Human Genetics at Baylor College of Funding Information: We thank Kees van Roozendaal and Rolph Pfundt for helpful discussions. We thank Kris Roberts, Rachel Coe, Liza Mak, and Michelle Zhou for supporting the CAUSES Study.?The bioinformatics pipeline used for analysis of patient 1 data was based on that developed in the laboratory of Wyeth Wasserman, with intellectual contributions from Dave Arenillas, Phillip Richmond, Casper Shyr, Alison Matthews, and Maja Tarailo-Graovac.?The CAUSES study is funded by the Mining for Miracles (British Columbia Children's Hospital Foundation) and Genome British Columbia, with support from the British Columbia Provincial Health Services Authority and British Columbia Women's Hospital.?We thank the patients and families for their participation in this study. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Baylor Genetics Laboratories. The authors declare no conflict of interest. Investigators in the CAUSES Study include Shelin Adam, Christ?le du Souich, Alison M. Elliott, Anna Lehman, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, and Jan M. Friedman. Publisher Copyright: © 2018 Wiley Periodicals, Inc.
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