Regulatory de novo mutations underlying intellectual disability

被引：1

作者：

Vas, Matias G. De ^{[1
]}

Boulet, Fanny ^{[2
]}

Joshi, Shweta S. ^{[1
]}

Garstang, Myles G. ^{[2
,3
]}

Khan, Tahir N. ^{[2
,4
]}

Atla, Goutham ^{[1
,5
,6
]}

Parry, David ^{[7
]}

Moore, David ^{[8
]}

Cebola, Ines ^{[1
]}

Zhang, Shuchen ^{[9
]}

Cui, Wei ^{[9
]}

Lampe, Anne K. ^{[8
]}

Lam, Wayne W. ^{[8
]}

Ferrer, Jorge ^{[1
,5
,6
]}

Pradeepa, Madapura M. ^{[2
,3
]}

Atanur, Santosh S. ^{[1
,11
,12
]}

机构：

[1] Imperial Coll London, Dept Metab Digest & Reprod, Sect Genet & Genom, London, England

[2] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England

[3] Univ Essex, Sch Biol Sci, Colchester, England

[4] Natl Univ Med Sci, Dept Biol Sci, Rawalpindi, Pakistan

[5] Barcelona Inst Sci & Technol, Ctr Genom Regulat, Regulatory Genom & Diabet, Barcelona, Spain

[6] Ctr Invest Biomed Red Diabet & Enfermedades Metab, Barcelona, Spain

[7] Univ Edinburgh, MRC Human Genet Unit, Edinburgh, Scotland

[8] Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh, Scotland

[9] Imperial Coll London, Inst Reprod & Dev Biol, Fac Med, London, England

[10] Genom England, London, England

[11] Imperial Coll London, NIHR Imperial Biomed Res Ctr, ITMAT Data Sci Grp, London, England

[12] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Scotland

来源：

LIFE SCIENCE ALLIANCE | 2023年 / 6卷 / 05期

基金：

欧洲研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

lectual disability (ID) remains unknown; De novo mutations; SOX8; GENE; FRAMEWORK; ELEMENTS; CELLS; EXPRESSION; PROMOTER; INSIGHTS; VARIANTS; ACCURATE; COMPLEX;

D O I：

10.26508/lsa.202201843

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The genetic aetiology of a major fraction of patients with intel(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 brainspecific enhancers as compared with adult brain enhancers. DNMcontaining 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 allelespecific 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.

引用

页数：16

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