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Am J Hum Genet. 2017 May 4;100(5):725-736. doi: 10.1016/j.ajhg.2017.03.010.

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.

Author information

1
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK; South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
2
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
3
Child Neurology Unit, Foundation IRCCS C Besta Neurological Institute, Milan 20133, Italy.
4
Landeskrankenanstalten Salzburg, Kinderklinik Department of Pediatrics, Klinische Genetik, Salzburg 5020, Austria.
5
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland.
6
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust, Southampton SO16 6YD, UK.
7
West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Foundation Trust and University of Birmingham, Birmingham Health Partners, Birmingham B15 2TG, UK.
8
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. Electronic address: rahmanlab@icr.ac.uk.

Abstract

To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10-8), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10-14). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.

KEYWORDS:

EZH2; HIST1H1E; NSD1; epigenetic regulation; exome sequencing; intellectual disability; overgrowth syndrome; sotos syndrome; weaver syndrome

PMID:
28475857
PMCID:
PMC5420355
DOI:
10.1016/j.ajhg.2017.03.010
[Indexed for MEDLINE]
Free PMC Article

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