@article{6a27b90033c24b97ba5f50adbcd18d58,
title = "Regulatory de novo mutations underlying intellectual disability",
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.",
keywords = "Adult, Alleles, Biological Assay, Genes, Regulator, Humans, Intellectual Disability/genetics, Mutation/genetics",
author = "Vas, {Matias G. De} and Fanny Boulet and Joshi, {Shweta S.} and Garstang, {Myles G.} and Khan, {Tahir N.} and Goutham Atla and David Parry and David Moore and In{\^e}s Cebola and Shuchen Zhang and Wei Cui and Lampe, {Anne K.} and Lam, {Wayne W.} and Consortium, {Genomics England Research} and Jorge Ferrer and Pradeepa, {Madapura M.} and Atanur, {Santosh S.}",
note = "Funding Information: We thank the families of the affected children for their time and support for the research. We thank Prof Andrew Jackson for helpful discussions and for obtaining ethical approval for the study. We thank Mrs Sophie Shi for contributing to reagent generation. We also thank Dr Patrick Short and Dr Kaitlin Samocha, both from Sanger Institute, for providing a trinucleotide probability table and helpful discussion on a mutational model, respectively. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. 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{\textquoteright}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{\textquoteright}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.” Publisher Copyright: {\textcopyright} 2023 Rockefeller University Press. All rights reserved.",
year = "2023",
month = may,
day = "1",
doi = "10.26508/lsa.202201843",
language = "English",
volume = "6",
journal = "Life Science Alliance",
issn = "2575-1077",
publisher = "Rockefeller University Press",
number = "5",
}