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

Katrina Tatton-Brown, Chey Loveday, Shawn Yost, Matthew Clarke, Emma Ramsay, Anna Zachariou, Anna Elliott, Harriet Wylie, Anna Ardissone, Olaf Rittinger, Fiona Stewart, I. Karen Temple, Trevor Cole, Shazia Mahamdallie, Sheila Seal, Elise Ruark, Nazneen Rahman, Childhood Overgrowth Collaboration

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)725-736
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - May 4 2017


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability'. Together they form a unique fingerprint.

Cite this