%0 Journal Article
%T Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability
%A Anna Ardissone
%A Anna Elliott
%A Anna Zachariou
%A Chey Loveday
%A Childhood Overgrowth Collaboration
%A Elise Ruark
%A Emma Ramsay
%A Fiona Stewart
%A Harriet Wylie
%A I. Karen Temple
%A Katrina Tatton-Brown
%A Matthew Clarke
%A Olaf Rittinger
%A Shawn Yost
%A Shazia Mahamdallie
%A Sheila Seal
%A Trevor Cole
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2017.03.010
%X 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 ¡Ý+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¡ªNSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED¡ªaccounted 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 ¡Á 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 ¡Á 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
%K overgrowth syndrome
%K epigenetic regulation
%K exome sequencing
%K intellectual disability
%K sotos syndrome
%K weaver syndrome
%K HIST1H1E
%K NSD1
%K EZH2
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420355/