Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.
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Date
2017-05-04ICR Author
Author
Tatton-Brown, K
Loveday, C
Yost, S
Clarke, M
Ramsay, E
Zachariou, A
Elliott, A
Wylie, H
Ardissone, A
Rittinger, O
Stewart, F
Temple, IK
Cole, T
Childhood Overgrowth Collaboration,
Mahamdallie, S
Seal, S
Ruark, E
Rahman, N
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Childhood Overgrowth Collaboration
Humans
Neoplasms
Intracellular Signaling Peptides and Proteins
DNA-Binding Proteins
Nuclear Proteins
Histones
Transcription Factors
Sequence Analysis, DNA
Developmental Disabilities
Gene Expression Regulation
Epigenesis, Genetic
Amino Acid Sequence
Linkage Disequilibrium
Mutation
Adolescent
Child
Child, Preschool
Infant
Female
Male
Genome-Wide Association Study
Genetic Loci
Intellectual Disability
Enhancer of Zeste Homolog 2 Protein
DNA (Cytosine-5-)-Methyltransferases
Histone Methyltransferases
Research team
Genetic Susceptibility
Language
eng
Date accepted
2017-03-24
License start date
2017-05
Citation
American journal of human genetics, 2017, 100 (5), pp. 725 - 736
Publisher
CELL PRESS