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De novo mutations in regulatory elements in neurodevelopmental disorders
Open accessPublished version of a preprint
Abstract
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.
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“Direct functional genomic exploration of accessible and disease-relevant tissues from patients using RNA sequencing and DNA methylation assays30,31 can identify previously cryptic causal genetic variants, particularly in under-explored regions outside protein-coding genes32,33.”
From A brief history of human disease genetics (2020) · cites this paper as [32]
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“This is in contrast to comparisons relying on LD blocks or the assignment by the closest gene, where the overlaps with methods that directly assess chromatin are less substantial (Short et al., 2018; Whalen and Pollard, 2018).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Short et al., 2018
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Metadata
- Authors
- Short, P. J., McRae, J. F., Gallone, G., Sifrim, A., Won, H., Geschwind, D. H., Wright, C. F., Firth, H. V., FitzPatrick, D. R., Barrett, J. C., & Hurles, M. E.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of California, Los Angeles (US)
- University of Exeter (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Western General Hospital (GB)
- Corresponding author
- Hurles, Matthew E.
- ORCID
- Venue
- Nature
- Published
- 2018-03
- Volume
- 555
- Issue
- 7698
- Pages
- 611-616
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5912909
- OpenAlex
- W2599110791
- Cited by
- 274
- References
- 56
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 34 · 2023: 22 · 2022: 39 · 2021: 43 · 2020: 33 · 2019: 48 · 2018: 22
- FWCI
- 22.02
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (WT 098051, 098051)
- Medical Research Council (MC_UU_00007/3)
- National Institute of Mental Health (U01MH105666, R01MH110927, R00MH113823, K99MH113823)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- de novo mutations, regulatory elements, neurodevelopmental disorders, recurrent mutations, rare variants, genetic heterogeneity
- MeSH terms
- Brain, Developmental Disabilities, Female, Fetus, Humans, Male, Mutation, Regulatory Sequences, Nucleic Acid, Conserved Sequence, Evolution, Molecular, Exome, Neurodevelopmental Disorders
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