Cited by 288Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

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De novo mutations in regulatory elements in neurodevelopmental disorders

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Short, Patrick J., McRae, Jeremy F., Gallone, Giuseppe, Sifrim, Alejandro, Won, Hyejung, Geschwind, Daniel H., Wright, Caroline F., Firth, Helen V., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E.·2018·Nature

DOI 10.1038/nature25983PMC PMC5912909

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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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Additional file 13 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
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Additional file 2 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
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Additional file 19 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599780
Additional file 6 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599741
Additional file 17 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599774
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Additional file 4 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
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Additional file 15 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599768
Additional file 14 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599765
Additional file 7 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599744
Additional file 5 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599738
Additional file 20 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599783
Additional file 9 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599750
Additional file 3 of Genetic effects of sequence-conserved enhancer-like elements on human complex traits
Zhu, X., Ma, S., & Wong, W. H. (2024) · Figshare · doi:10.6084/m9.figshare.26658229
Additional file 12 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599759
Additional file 1 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599726
Additional file 8 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599747
Additional file 16 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599771
Additional file 2 of Genetic effects of sequence-conserved enhancer-like elements on human complex traits
Zhu, X., Ma, S., & Wong, W. H. (2024) · Figshare · doi:10.6084/m9.figshare.24934550
Additional file 3 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599732
Additional file 10 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599753
Additional file 11 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599756
Additional file 18 of Identification and characterization of transcribed enhancers during cerebellar development through enhancer RNA analysis
Ramirez, M., Robert, R., Yeung, J., Wu, J. P. H., Abdalla-Wyse, A., & Goldowitz, D. (2024) · Figshare · doi:10.6084/m9.figshare.26599777
Additional file 1 of Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery
Zhang, X., Theotokis, P. I., Li, N., Wright, C. F., Samocha, K. E., Whiffin, N., & Ware, J. S. (2024) · Figshare · doi:10.6084/m9.figshare.26265039
Self-citation
Additional file 2 of Imbalance of flight–freeze responses and their cellular correlates in the Nlgn3−/y rat model of autism
Anstey, N. J., Kapgal, V., Tiwari, S., Watson, T. C., Toft, A. K. H., Dando, O., Inkpen, F. H., Baxter, P. S., Kozić, Z., Jackson, A. D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20336962
Copy number variants (CNVs) interfere with human accelerated regions (HARs) in neurodevelopmental disorders: a large-scale cohort study
Iuditskaia, M. E., Semina, E. V., Pankratova, E. D., Kurinnaia, O. S., Guldan, E. V., Abasov, E. H., Iourov, I. Y., & Chaika, Y. A. (2026) · Scientific Reports · doi:10.1038/s41598-026-76092-w
“Copy number variations (CNVs) — deletions and duplications of genomic segments — play a particularly important role in the genetic architecture of NDDs and are associated with a broad spectrum of neurodevelopmental and neuropsychiatric phenotypes [40,41,43].”
Germline functional variants contribute to neurodevelopmental trajectories in children with autism spectrum disorder or intellectual disability
Ahn, S., Oh, J.-H., Kang, Y. G., Oh, D. E., Lee, T., Kim, S., Hyun, Y., Sung, C. O., & Kim, H.-W. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111655
Nouvelles approches de prédiction de la pathogénicité des mutations
Corcuff, M. (2022) · theses.fr (ABES) · doi:10.70675/c935311cz1cc8z4cfdzbe8az384966c33808
Large-scale genomic investigation into factors contributing to metabolic derangements and their comorbidity
Pascat, V. (2024) · theses.fr (ABES) · doi:10.70675/ee25a652z0aadz46c1z83f4zd89e14223bfb
Postnatal relevance of HOXA5 transcription factor in cerebellum-associated behaviors and disorders
Glibert, H., Bridoux, L., Moens, C., Schakman, O., Jeannotte, L., Clotman, F., & Gofflot, F. (2026) · Behavioral and Brain Functions · doi:10.1186/s12993-026-00343-z
“Additionally, regulatory elements of ASD-risk genes have been found to exhibit higher rates of de novo mutations in ASD patients [82, 83].”
Phenotype-informed trio analysis reveals a multi-layered fetal genomic architecture in preterm birthPreprint
Dauengauer‐Kirlienė, S., Pranckėnienė, L., Letukienė, A., Puzeras, F., Domarkienė, I., & Urnikytė, A. (2026) · Research Square · doi:10.21203/rs.3.rs-9876120/v1
Mechanisms underlying disease-causing variants in promoters and enhancers
Long, H. K., Wu, K., Barkham, R. S., & Bickmore, W. A. (2026) · Nature Genetics · doi:10.1038/s41588-026-02743-3
“For neurodevelopmental disorders, estimates suggest that only up to 5% patients without a genetic diagnosis have a disease-causing noncoding variant 37,38 .”
Identification of novel CDK19 variants and Drosophila-based in vivo functional evidence supporting pathogenicity in neurodevelopmental disorders
Koh, H. Y., Sahu, R. K., Kim, S. D., TANAKA, T., Grewal, K. S., Liao, J. Z., Shim, Y.-K., Garg, R., Krey, I., Bothe, V., et al. (2026) · Genetics in Medicine · doi:10.1016/j.gim.2026.102735
A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care
Geysens, M., Souche, E., Baroni, M. C., Benoit, V., Beyltjens, T., Bossuyt, W., Bours, V., Crabbé, M., Croes, D., De Smet, M., et al. (2026) · Genome Medicine · doi:10.1186/s13073-026-01771-2
“GS is gradually revealing the involvement of non-coding variants in developmental and numerous other disorders [7–9] prompting questions about the proportion of missed diagnoses when analyses are confined to the exome.”
Reading strong selection from modest GWAS hits
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Genetics of Autism
Khan, M., RUTTER, M., Thapar, A., & Yuen, R. K. C. (2026) · Wiley eBooks · doi:10.1002/9781394389933.ch16

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: Short, Patrick J.
McRae, Jeremy F.
Sifrim, Alejandro
Won, Hyejung
Geschwind, Daniel H.
Wright, Caroline F.
Firth, Helen V.
FitzPatrick, David R.
Barrett, Jeffrey C.
Hurles, Matthew E.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-03
Volume: 555
Issue: 7698
Pages: 611-616
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature25983
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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De novo mutations in regulatory elements in neurodevelopmental disorders

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