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Regulatory de novo mutations underlying intellectual disability

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 proband...

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Autores principales: De Vas, Matias G, Boulet, Fanny, Joshi, Shweta S, Garstang, Myles G, Khan, Tahir N, Atla, Goutham, Parry, David, Moore, David, Cebola, Inês, Zhang, Shuchen, Cui, Wei, Lampe, Anne K, Lam, Wayne W, Ferrer, Jorge, Pradeepa, Madapura M, Atanur, Santosh S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978454/
https://www.ncbi.nlm.nih.gov/pubmed/36854624
http://dx.doi.org/10.26508/lsa.202201843
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author De Vas, Matias G
Boulet, Fanny
Joshi, Shweta S
Garstang, Myles G
Khan, Tahir N
Atla, Goutham
Parry, David
Moore, David
Cebola, Inês
Zhang, Shuchen
Cui, Wei
Lampe, Anne K
Lam, Wayne W
Ferrer, Jorge
Pradeepa, Madapura M
Atanur, Santosh S
author_facet De Vas, Matias G
Boulet, Fanny
Joshi, Shweta S
Garstang, Myles G
Khan, Tahir N
Atla, Goutham
Parry, David
Moore, David
Cebola, Inês
Zhang, Shuchen
Cui, Wei
Lampe, Anne K
Lam, Wayne W
Ferrer, Jorge
Pradeepa, Madapura M
Atanur, Santosh S
author_sort De Vas, Matias G
collection PubMed
description 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.
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spelling pubmed-99784542023-03-03 Regulatory de novo mutations underlying intellectual disability De Vas, Matias G Boulet, Fanny Joshi, Shweta S Garstang, Myles G Khan, Tahir N Atla, Goutham Parry, David Moore, David Cebola, Inês Zhang, Shuchen Cui, Wei Lampe, Anne K Lam, Wayne W Ferrer, Jorge Pradeepa, Madapura M Atanur, Santosh S Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2023-02-28 /pmc/articles/PMC9978454/ /pubmed/36854624 http://dx.doi.org/10.26508/lsa.202201843 Text en © 2023 De Vas et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
De Vas, Matias G
Boulet, Fanny
Joshi, Shweta S
Garstang, Myles G
Khan, Tahir N
Atla, Goutham
Parry, David
Moore, David
Cebola, Inês
Zhang, Shuchen
Cui, Wei
Lampe, Anne K
Lam, Wayne W
Ferrer, Jorge
Pradeepa, Madapura M
Atanur, Santosh S
Regulatory de novo mutations underlying intellectual disability
title Regulatory de novo mutations underlying intellectual disability
title_full Regulatory de novo mutations underlying intellectual disability
title_fullStr Regulatory de novo mutations underlying intellectual disability
title_full_unstemmed Regulatory de novo mutations underlying intellectual disability
title_short Regulatory de novo mutations underlying intellectual disability
title_sort regulatory de novo mutations underlying intellectual disability
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978454/
https://www.ncbi.nlm.nih.gov/pubmed/36854624
http://dx.doi.org/10.26508/lsa.202201843
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