Send to

Choose Destination
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

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.
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
Child Neurology Unit, Foundation IRCCS C Besta Neurological Institute, Milan 20133, Italy.
Landeskrankenanstalten Salzburg, Kinderklinik Department of Pediatrics, Klinische Genetik, Salzburg 5020, Austria.
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland.
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.
West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Foundation Trust and University of Birmingham, Birmingham Health Partners, Birmingham B15 2TG, UK.
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:


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.


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

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center