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De novo mutations in fetal brain specific enhancers play a significant role in severe intellectual disability

Matias G De Vas, Myles G Garstang, Shweta S Joshi, Tahir Khan, Goutham Atla, David Parry, David Moore, Ines Cebola, Shuchen Zhang, Wei Cui, Anne K Lampe, Wayne W Lam, David R FitzPatrick, Madapura M Pradeepa, View ORCID ProfileSantosh S Atanur
doi: https://doi.org/10.1101/621029
Matias G De Vas
Department of Medicine, Faculty of Medicine, Imperial College London, London, W12 0NN
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Myles G Garstang
Blizard institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2ATSchool of Biological Sciences, University of Essex, Colchester, CO4 3SQ
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Shweta S Joshi
Department of Medicine, Faculty of Medicine, Imperial College London, London, W12 0NN
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Tahir Khan
Blizard institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT
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Goutham Atla
Department of Medicine, Faculty of Medicine, Imperial College London, London, W12 0NNCIBER de Diabetes y Enfermedades Metabólicas Asociadas, SpainCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
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David Parry
MRC Human Genetics Unit, University of Edinburgh, EH4 2XU
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David Moore
South-East Scotland Regional Genetics Service, Western General Hospital, Edinburgh EH4 2XU
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Ines Cebola
Department of Medicine, Faculty of Medicine, Imperial College London, London, W12 0NN
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Shuchen Zhang
Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, W12 0NN
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Wei Cui
Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, W12 0NN
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Anne K Lampe
South-East Scotland Regional Genetics Service, Western General Hospital, Edinburgh EH4 2XU
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Wayne W Lam
South-East Scotland Regional Genetics Service, Western General Hospital, Edinburgh EH4 2XU
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David R FitzPatrick
MRC Human Genetics Unit, University of Edinburgh, EH4 2XU
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Madapura M Pradeepa
Blizard institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2ATSchool of Biological Sciences, University of Essex, Colchester, CO4 3SQ
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  • For correspondence: satanur@ic.ac.uk p.m.madapura@qmul.ac.uk
Santosh S Atanur
Department of Medicine, Faculty of Medicine, Imperial College London, London, W12 0NNPrevious institute: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU
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  • ORCID record for Santosh S Atanur
  • For correspondence: satanur@ic.ac.uk p.m.madapura@qmul.ac.uk
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Abstract

The genetic aetiology of a large proportion of intellectual disability (ID) cases still remains undiagnosed as de novo mutations (DNMs) in protein coding regions of the genome explain only 35-40% of the cases1,2. We sequenced whole genomes of 70 individuals, including 24 ID probands, to identify potentially pathogenic DNMs at distal cis-regulatory elements, as they may explain some of these genetically undiagnosed ID cases. In our cohort, DNMs were significantly enriched in fetal brain specific enhancers that were intolerant to mutations within the human population. The majority of these enhancer DNMs showed a significant effect on enhancer activity compared to the reference alleles when tested using luciferase reporter assays. Furthermore, CRISPR interference of CSMD1 enhancer resulted in overexpression of the neurogenesis gene CSMD1 suggesting that the disruption of a transcriptional repressor binding site due to an enhancer DNM could be a potential cause of ID in one of the patients. Taken together, our results demonstrate that DNMs in tissue specific enhancers play an important role in the aetiology of ID.

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Posted April 28, 2019.
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De novo mutations in fetal brain specific enhancers play a significant role in severe intellectual disability
Matias G De Vas, Myles G Garstang, Shweta S Joshi, Tahir Khan, Goutham Atla, David Parry, David Moore, Ines Cebola, Shuchen Zhang, Wei Cui, Anne K Lampe, Wayne W Lam, David R FitzPatrick, Madapura M Pradeepa, Santosh S Atanur
bioRxiv 621029; doi: https://doi.org/10.1101/621029
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De novo mutations in fetal brain specific enhancers play a significant role in severe intellectual disability
Matias G De Vas, Myles G Garstang, Shweta S Joshi, Tahir Khan, Goutham Atla, David Parry, David Moore, Ines Cebola, Shuchen Zhang, Wei Cui, Anne K Lampe, Wayne W Lam, David R FitzPatrick, Madapura M Pradeepa, Santosh S Atanur
bioRxiv 621029; doi: https://doi.org/10.1101/621029

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