Imperial College London
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DrSantoshAtanur

Faculty of Medicine, National Heart & Lung Institute

Honorary Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2739santosh.atanur

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{De:2019:10.1101/621029,
author = {De, Vas MG and Garstang, MG and Joshi, SS and Khan, TN and Atla, G and Parry, D and Moore, D and Cebola, I and Zhang, S and Cui, W and Lampe, AK and Lam, WW and FitzPatrick, DR and Ferrer, J and Pradeepa, MM and Atanur, SS},
doi = {10.1101/621029},
title = {<i>De novo</i> variants in population constrained fetal brain enhancers and intellectual disability},
url = {http://dx.doi.org/10.1101/621029},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. <jats:italic>De novo</jats:italic> mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We sequenced 70 whole genomes from 24 ID probands and their unaffected parents and analyzed 30 previously sequenced genomes from exome-negative ID probands.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found that DNVs were selectively enriched in fetal brain-specific enhancers that show purifying selection in human population. DNV containing enhancers were associated with genes that show preferential expression in the pre-frontal cortex, have been previously implicated in ID or related disorders, and exhibit intolerance to loss of function variants. DNVs from ID probands preferentially disrupted putative binding sites of neuronal transcription factors, as compared to DNVs from healthy individuals and most showed allele-specific enhancer activity. In addition, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (<jats:italic>CSMD1</jats:italic>, <jats:italic>OLFM1</jats:italic> and <jats:italic>POU3F3)</jats:italic>. Moreover, CRISPR-based perturbation of a DNV-containing enhancer caused <jats:italic>CSMD1</jats:italic> overexpression and abnormal expression of neurodevelopmental regulators.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results, therefore, provide new evidence to indicate that DNVs in constrained fetal brain-speci
AU  - De,Vas MG
AU  - Garstang,MG
AU  - Joshi,SS
AU  - Khan,TN
AU  - Atla,G
AU  - Parry,D
AU  - Moore,D
AU  - Cebola,I
AU  - Zhang,S
AU  - Cui,W
AU  - Lampe,AK
AU  - Lam,WW
AU  - FitzPatrick,DR
AU  - Ferrer,J
AU  - Pradeepa,MM
AU  - Atanur,SS
DO  - 10.1101/621029
PY  - 2019///
TI  - <i>De novo</i> variants in population constrained fetal brain enhancers and intellectual disability
UR  - http://dx.doi.org/10.1101/621029
ER  -
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