dc.contributor.author | Tatton-Brown, K | |
dc.contributor.author | Loveday, C | |
dc.contributor.author | Yost, S | |
dc.contributor.author | Clarke, M | |
dc.contributor.author | Ramsay, E | |
dc.contributor.author | Zachariou, A | |
dc.contributor.author | Elliott, A | |
dc.contributor.author | Wylie, H | |
dc.contributor.author | Ardissone, A | |
dc.contributor.author | Rittinger, O | |
dc.contributor.author | Stewart, F | |
dc.contributor.author | Temple, IK | |
dc.contributor.author | Cole, T | |
dc.contributor.author | Childhood Overgrowth Collaboration, | |
dc.contributor.author | Mahamdallie, S | |
dc.contributor.author | Seal, S | |
dc.contributor.author | Ruark, E | |
dc.contributor.author | Rahman, N | |
dc.date.accessioned | 2017-11-01T15:16:50Z | |
dc.date.issued | 2017-05-04 | |
dc.identifier.citation | American journal of human genetics, 2017, 100 (5), pp. 725 - 736 | |
dc.identifier.issn | 0002-9297 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/891 | |
dc.identifier.eissn | 1537-6605 | |
dc.identifier.doi | 10.1016/j.ajhg.2017.03.010 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | 725 - 736 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Childhood Overgrowth Collaboration | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Nuclear Proteins | |
dc.subject | Histones | |
dc.subject | Transcription Factors | |
dc.subject | Sequence Analysis, DNA | |
dc.subject | Developmental Disabilities | |
dc.subject | Gene Expression Regulation | |
dc.subject | Epigenesis, Genetic | |
dc.subject | Amino Acid Sequence | |
dc.subject | Linkage Disequilibrium | |
dc.subject | Mutation | |
dc.subject | Adolescent | |
dc.subject | Child | |
dc.subject | Child, Preschool | |
dc.subject | Infant | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Genome-Wide Association Study | |
dc.subject | Genetic Loci | |
dc.subject | Intellectual Disability | |
dc.subject | Enhancer of Zeste Homolog 2 Protein | |
dc.subject | DNA (Cytosine-5-)-Methyltransferases | |
dc.subject | Histone Methyltransferases | |
dc.title | Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-03-24 | |
rioxxterms.versionofrecord | 10.1016/j.ajhg.2017.03.010 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | American journal of human genetics | |
pubs.issue | 5 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Genetic Susceptibility | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Genetic Susceptibility | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Genetic Susceptibility | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Genetic Susceptibility | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 100 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Genetic Susceptibility | |
dc.contributor.icrauthor | Clarke, Matthew | |