Regulatory de novo mutations underlying intellectual disability

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Vas, Matías G. de
  • dc.contributor.author Boulet, Fanny
  • dc.contributor.author Joshi, Shweta S.
  • dc.contributor.author Garstang, Myles G.
  • dc.contributor.author Khan, Tahir N.
  • dc.contributor.author Atla, Goutham
  • dc.contributor.author Parry, David
  • dc.contributor.author Moore, David
  • dc.contributor.author Cebola, Inês
  • dc.contributor.author Zhang, Shuchen
  • dc.contributor.author Cui, Wei, 1970-
  • dc.contributor.author Lampe, Anne K.
  • dc.contributor.author Lam, Wayne W.
  • dc.contributor.author Genomics England Research Consortium
  • dc.contributor.author Ferrer, Jorge
  • dc.contributor.author Pradeepa, Madapura M.
  • dc.contributor.author Atanur, Santosh S.
  • dc.date.accessioned 2023-06-08T06:49:04Z
  • dc.date.available 2023-06-08T06:49:04Z
  • dc.date.issued 2023
  • dc.description.abstract The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, and POU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.
  • dc.description.sponsorship This work was funded by grants from the Wellcome Trust Institute Strategic Support and National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P70888) obtained by SS Atanur. J Ferrer and MG De Vas’s work was funded by grants from the Wellcome Trust (WT101033 to J Ferrer), Medical Research Council (MR/L02036X/1 to J Ferrer), and European Research Council Advanced Grant (789055 to J Ferrer). MM Pradeepa’s lab is funded by the UKRI/MRC (MR/T000783/1), and Barts charity (MGU0475) grants. TN Khan was partially supported by the Government of Pakistan under the PSDP project “Development of National University of Medical Sciences (NUMS), Rawalpindi.”
  • dc.format.mimetype application/pdf
  • dc.identifier.citation De Vas MG, Boulet F, Joshi SS, Garstang MG, Khan TN, Atla G, Parry D, Moore D, Cebola I, Zhang S, Cui W, Lampe AK, Lam WW; Genomics England Research Consortium; Ferrer J, Pradeepa MM, Atanur SS. Regulatory de novo mutations underlying intellectual disability. Life Sci Alliance. 2023 Feb 28;6(5):e202201843. DOI: 10.26508/lsa.202201843
  • dc.identifier.doi http://dx.doi.org/10.26508/lsa.202201843
  • dc.identifier.issn 2575-1077
  • dc.identifier.uri http://hdl.handle.net/10230/57113
  • dc.language.iso eng
  • dc.publisher Life Science Alliance
  • dc.relation.ispartof Life Sci Alliance. 2023 Feb 28;6(5):e202201843
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
  • dc.rights © 2023 De Vas et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.title Regulatory de novo mutations underlying intellectual disability
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)