De novo mutations in regulatory elements in neurodevelopmental disorders
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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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Direct functional genomic exploration of accessible and disease-relevant tissues from patients using RNA sequencing and DNA methylation assays can identify previously cryptic causal genetic variants, particularly in under-explored noncoding regions.
“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]
Overlaps with methods that directly assess chromatin are less substantial for comparisons relying on linkage disequilibrium blocks or closest-gene assignment.
“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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“It is estimated that up to 3% of all patients with negative exomes could be explained by variants in the non-coding, regulatory regions that would be detectable by genome sequencing (316) and could be further assessed through technologies such as RNA-sequencing (317) and genome-wide methylation studies (319, 320).”
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Wright, C. F., Campbell, P. H., Eberhardt, R. Y., Aitken, S., Perrett, D., Brent, S., Danecek, P., Gardner, E. J., Chundru, V. K., Lindsay, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2209046 · Cited by 222 · see citing works
Self-citationClinical implementation of RNA sequencing for Mendelian disease diagnostics
Yépez, V. A., Gušić, M., Kopajtich, R., Mertes, C., Smith, N. H., Alston, C. L., Ban, R., Beblo, S., Berutti, R., Blessing, H., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01019-9 · Cited by 210 · see citing works
“It appears especially important for neurodevelopmental disorders, where de novo variants are often found in haploinsufficient genes or regulatory non-coding regions [107, 108].”
BackgroundEbbert, M., Jensen, T. D., Jansen‐West, K. R., Sens, J. P., Reddy, J. S., Ridge, P. G., Kauwe, J. S. K., Belzil, V., Pregent, L., Carrasquillo, M. M., et al. (2019) · Genome biology · doi:10.1186/s13059-019-1707-2 · Cited by 192 · see citing works
Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
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Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
Epilepsy genetics: clinical impacts and biological insights
Ellis, C. A., Petrovski, S., & Berkovic, S. F. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30269-8 · Cited by 136 · see citing works
Carrier screening for recessive disorders
Antonarakis, S. E. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0134-2 · Cited by 129 · see citing works
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NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements
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Genome sequencing and implications for rare disorders
Posey, J. E. (2019) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-019-1127-0 · Cited by 110 · see citing works
“Analysis of de novo variants from trio-GS (proband + parents) data is yet another approach to identify putative pathogenic noncoding variants in individuals with apparently sporadic disease [98], and a deep-sequencing approach can enable detection of low-level parental germline mosaicism, which can impact recurrence r…”
BackgroundLiu, Z., Zhu, L., Roberts, R. A., & Tong, W. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.08.006 · Cited by 108 · see citing works
“For example, causative genetic variants, such as de novo mutations, were discovered in various rare diseases with a shallow frequency and a low penetrance rate [96].”
BackgroundNeurobiological functions of transcriptional enhancers
Nord, A. S., & West, A. E. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0538-5 · Cited by 100 · see citing works
Enhancer Domains Predict Gene Pathogenicity and Inform Gene Discovery in Complex Disease
Wang, X., & Goldstein, D. B. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.01.012 · Cited by 99 · see citing works
The performance of genome sequencing as a first-tier test for neurodevelopmental disorders
van der Sanden, B. P. G. H., Schobers, G., Corominas Galbany, J., Koolen, D. A., Sinnema, M., van Reeuwijk, J., Stumpel, C. T. R. M., Kleefstra, T., de Vries, B. B. A., Ruiterkamp-Versteeg, M., et al. (2023) · European Journal of Human Genetics · doi:10.1038/s41431-022-01185-9 · Cited by 97 · see citing works
Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases
Zurek, B., Ellwanger, K., Vissers, L. E. L. M., Schüle, R., Synofzik, M., Töpf, A., de Voer, R. M., Laurie, S., Matalonga, L., Gilissen, C., et al. (2021) · European Journal of Human Genetics · doi:10.1038/s41431-021-00859-0 · Cited by 99 · see citing works
Lee, D. S. M., Ghanem, L. R., & Barash, Y. (2020) · Nature Communications · doi:10.1038/s41467-020-14404-y · Cited by 97 · see citing works
Pathogenicity and selective constraint on variation near splice sitesPreprint
Lord, J., Gallone, G., Short, P., McRae, J. F., Ironfield, H., Wynn, E. H., Gerety, S. S., He, L., Kerr, B. A., Johnson, D. S., et al. (2018) · Genome Research · doi:10.1101/gr.238444.118 · Cited by 93 · see citing works
Self-citationEssential genetic findings in neurodevelopmental disorders
Cardoso, A. R., Lopes‐Marques, M., Silva, R. M., Serrano, C., Amorim, A., Prata, M. J., & Azevedo, L. (2019) · Human Genomics · doi:10.1186/s40246-019-0216-4 · Cited by 87 · see citing works
“protein-coding genes with a high degree of haploinsufficiency or in regulatory elements involved in alternative splicing, in transcriptional regulation (enhancer and promoter), and in conserved non-coding sequences [41].”
BackgroundIncreased enhancer–promoter interactions during developmental enhancer activation in mammals
Chen, Z., Snetkova, V., Bower, G., Jacinto, S. H., Clock, B., Dizehchi, A., Barozzi, I., Mannion, B. J., Alcaina‐Caro, A., López-Rı́os, J., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01681-2 · Cited by 84 · see citing works
“…away (chr3:99,000,000–99,900,000, mm10) 76 in the forelimb. e , Two de novo rare variants identified in patients with neurodevelopmental disorders 77,78 are in the hs1523 forebrain–midbrain enhancer (green bar), which forms strong significant interactions with the promoter of Foxg1 (highlighted…”
Ranking of non-coding pathogenic variants and putative essential regions of the human genome
Wells, A. C., Heckerman, D. E., Torkamani, A., Li, Y., Sebat, J. L., Ren, B., Telenti, A., & di Iulio, J. (2019) · Nature Communications · doi:10.1038/s41467-019-13212-3 · Cited by 76 · see citing works
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Invited Review: Epigenetics in neurodevelopment
Salinas, R. D., Connolly, D. R., & Song, H. (2020) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12608 · Cited by 81 · see citing works
Wang, W., Corominas, R., & Lin, G. N. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00258 · Cited by 70 · see citing works
Wright, C. F., Quaife, N. M., Ramos-Hernández, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.04.025 · Cited by 68 · see citing works
Self-citationGenetic basis of mitochondrial diseases
Gušić, M., & Prokisch, H. (2021) · FEBS Letters · doi:10.1002/1873-3468.14068 · Cited by 76 · see citing works
“Finally, de novo mutations are enriched in neurodevelopmental disorders and could provide a diagnosis for up to 3% of currently undiagnosed patients [211].”
The Genetics of Intellectual Disability
Jansen, S., Vissers, L. E. L. M., & de Vries, B. B. A. (2023) · Brain Sciences · doi:10.3390/brainsci13020231 · Cited by 81 · see citing works
“However, no single element reached statistical significance and could be regarded as causative for NDD [95].”
BackgroundPerenthaler, E., Yousefi, S., Niggl, E., & Barakat, T. S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00352 · Cited by 71 · see citing works
“Although only very few large-scale genetic studies have investigated the role of the non-coding genome in genetic disorders (Doan et al., 2016; Devanna et al., 2018; Short et al., 2018) it is clear from the number of excellent studies that have recently been published (Lettice et al.”
BackgroundGenetic testing for kidney disease of unknown etiology
Hays, T., Groopman, E., & Gharavi, A. G. (2020) · Kidney International · doi:10.1016/j.kint.2020.03.031 · Cited by 73 · see citing works
Genome analysis and knowledge-driven variant interpretation with TGex
Dahary, D., Golan, Y., Mazor, Y., Zelig, O., Barshir, R., Twik, M., Stein, T. I., Rosner, G., Kariv, R., Chen, F., et al. (2019) · BMC Medical Genomics · doi:10.1186/s12920-019-0647-8 · Cited by 71 · see citing works
“SV analysis is exemplified by a list of recurrently mutated regulatory elements discovered in a cohort of patients with neurodevelopmental disorders [63].”
BackgroundGenomic Diagnosis for Pediatric Disorders: Revolution and Evolution
Lalonde, E., Rentas, S., Lin, F., Dulik, M. C., Skraban, C. M., & Spinner, N. B. (2020) · Frontiers in Pediatrics · doi:10.3389/fped.2020.00373 · Cited by 69 · see citing works
Enhancers: bridging the gap between gene control and human disease
Karnuta, J. M., & Scacheri, P. C. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy167 · Cited by 68 · see citing works
Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese
Wang, C., Dai, J., Qin, N., Fan, J., Ma, H., Chen, C., An, M., Zhang, J., Yan, C., Gu, Y., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.08.013 · Cited by 70 · see citing works
The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders
Turner, T. N., & Eichler, E. E. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.11.002 · Cited by 69 · see citing works
The human and non-human primate developmental GTEx projects
Coorens, T. H. H., Guillaumet-Adkins, A., Kovner, R., Linn, R. L., Roberts, V. H. J., Sule, A. D., Hoose, P. M. V., Bell, T., Blanchard, T., Hernandez, R., et al. (2025) · Nature · doi:10.1038/s41586-024-08244-9 · Cited by 67 · see citing works
Caron, B., Luo, Y., & Rausell, A. (2019) · Genome biology · doi:10.1186/s13059-019-1634-2 · Cited by 62 · see citing works
Rowlands, C. F., Thomas, H. B., Lord, J., Wai, H. A., Arno, G., Beaman, G. M., Sergouniotis, P. I., Gomes-Silva, B., Campbell, C., Gossan, N. C., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-99747-2 · Cited by 66 · see citing works
Interpreting the impact of noncoding structural variation in neurodevelopmental disorders
D’haene, E., & Vergult, S. (2020) · Genetics in Medicine · doi:10.1038/s41436-020-00974-1 · Cited by 59 · see citing works
Disrupting upstream translation in mRNAs is associated with human disease
Lee, D. S. M., Park, J., Kromer, A., Baras, A., Rader, D. J., Ritchie, M. D., Ghanem, L. R., & Barash, Y. (2021) · Nature Communications · doi:10.1038/s41467-021-21812-1 · Cited by 65 · see citing works
De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis
Alonso-González, A., Rodriguez‐Fontenla, C., & Carracedo, Á. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00406 · Cited by 65 · see citing works
Diagnosing rare diseases after the exomePreprint
Frésard, L., & Montgomery, S. B. (2018) · Molecular Case Studies · doi:10.1101/mcs.a003392 · Cited by 61 · see citing works
“…Hoffman-Andrews 2017); if multiple variants are responsible for the pathology, in two ormore genes (Liu et al. 2007; Sambuughin et al. 2018); if it is a structural variant not properly caught through exome sequencing (Merker et al. 2018); and in cases in which it is not exonic (Short et al. 2018).”
BackgroundMethodInfluentialContribution of retrotransposition to developmental disorders
Gardner, E. J., Prigmore, E., Gallone, G., Danecek, P., Samocha, K. E., Handsaker, J., Gerety, S. S., Ironfield, H., Short, P., Sifrim, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12520-y · Cited by 58 · see citing works
Self-citationKushima, I., Nakatochi, M., Aleksić, B., Okada, T., Kimura, H., Kato, H., Morikawa, M., Inada, T., Ishizuka, K., Torii, Y., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.04.003 · Cited by 55 · see citing works
“Previous studies have reported that variants in these regulatory elements play a role in the risk for psychiatric disorders (47, 68, 69).”
BackgroundUncovering Missing Heritability in Rare Diseases
Maroilley, T., & Tarailo‐Graovac, M. (2019) · Genes · doi:10.3390/genes10040275 · Cited by 55 · see citing works
“For example, non-coding genome (~98% of the human genome) remains largely unexplored, yet emerging studies reinforce the importance of considering these variants in RD patients [42].”
BackgroundWang, C., Lv, H., Ling, X., Li, H., Diao, F., Dai, J., Du, J., Chen, T., Xi, Q., Zhao, Y., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00521-w · Cited by 55 · see citing works
Selection against archaic hominin genetic variation in regulatory regions
Telis, N., Aguilar, R., & Harris, K. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-01284-0 · Cited by 51 · see citing works
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project
Blakes, A. J. M., Wai, H. A., Davies, I., Moledina, H. E., Ruiz, A., Thomas, T., Bunyan, D. J., Thomas, N. S., Burren, C. P., Greenhalgh, L., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01087-x · Cited by 53 · see citing works
De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy
Hamanaka, K., Imagawa, E., Koshimizu, E., Miyatake, S., Tohyama, J., Yamagata, T., Miyauchi, A., Ekhilevitch, N., Nakamura, F., Kawashima, T., et al. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.02.011 · Cited by 53 · see citing works
Zhai, Y., Zhang, Z., Shi, P., Martin, D. M., & Kong, X. (2021) · Human Mutation · doi:10.1002/humu.24222 · Cited by 51 · see citing works
“coding variants are recognized genetic etiology in 13%–60% of NDD cases (Short et al., 2018; Wilfert et al., 2017).”
BackgroundResultKurki, M., Saarentaus, E., Pietiläinen, O. P. H., Gormley, P., Lal, D., Kerminen, S., Torniainen‐Holm, M., Hämäläinen, E., Rahikkala, E., Keski‐Filppula, R., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08262-y · Cited by 52 · see citing works
Recent Advances in Understanding the Genetic Architecture of Autism
Dias, C., & Walsh, C. A. (2020) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-121219-082309 · Cited by 53 · see citing works
“Both de novo and inherited noncoding variants have been implicated in autism risk (4, 7, 17, 67, 75, 81, 82).”
BackgroundResultA genome-wide scan statistic framework for whole-genome sequence data analysis
He, Z., Xu, B., Buxbaum, J. D., & Ionita‐Laza, I. (2019) · Nature Communications · doi:10.1038/s41467-019-11023-0 · Cited by 49 · see citing works
Perfect and imperfect views of ultraconserved sequences
Snetkova, V., Pennacchio, L. A., Visel, A., & Dickel, D. E. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00424-x · Cited by 45 · see citing works
Functional annotation of rare structural variation in the human brain
Han, L., Zhao, X., Benton, M. L., Perumal, T. M., Collins, R. L., Hoffman, G. E., Johnson, J., Sloofman, L. G., Wang, H. Z., Stone, M. R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16736-1 · Cited by 43 · see citing works
“Regulatory variants, particularly SVs, have the potential to alter the expression of many genes and previous work has already implicated de novo variants in fetal enhancers in risk for neurodevelopmental disorders 26 .”
Evolutionary conservation in noncoding genomic regions
Leypold, N. A., & Speicher, M. R. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.06.007 · Cited by 46 · see citing works
Hamanaka, K., Miyake, N., Mizuguchi, T., Miyatake, S., Uchiyama, Y., Tsuchida, N., Sekiguchi, F., Mitsuhashi, S., Tsurusaki, Y., Nakashima, M., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01042-w · Cited by 46 · see citing works
“We calculated the mutation rates of SNVs and small indels per gene using the trinucleotide-context model (https:// github. com/ pjsho rt/ dddMA PS) [17], which gives mutation rates in each trinucleotide context, as described in our previous report (script: https:// github. com/ haman akako hei/…”
BackgroundMethodWhole-genome sequencing of patients with rare diseases in a national health system
Turro, E., Astle, W. J., Mégy, K., Gräf, S., Greene, D. J., Shamardina, O., Allen, H. L., Sanchis‐Juan, A., Frontini, M., Thys, C., et al. (2021) · Yearbook of pediatric endocrinology · doi:10.1530/ey.18.14.6 · Cited by 44 · see citing works
Advances in mouse genetics for the study of human disease
Brown, S. D. M. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab153 · Cited by 43 · see citing works
Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders
Haghshenas, S., Bhai, P. S., Aref‐Eshghi, E., & Sadiković, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239303 · Cited by 42 · see citing works
Zug, R. (2022) · Biology Open · doi:10.1242/bio.058896 · Cited by 42 · see citing works
“…rare inherited loss-of-function mutations affecting haploinsufficient genes involved in transcriptional regulation and chromatin remodelling, but also haploinsufficient noncoding regulatory regions (Short et al., 2018; Turner and Eichler, 2019; Moyses-Oliveira et al., 2020; Parenti et al., 2020).”
Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?
Gegenhuber, B., & Tollkühn, J. (2019) · Genes · doi:10.3390/genes10060432 · Cited by 39 · see citing works
Multi-omic analysis elucidates the genetic basis of hydrocephalus
Hale, A. T., Bastarache, L. A., Morales, D. M., Wellons, J. C., Limbrick, D. D., & Gamazon, E. R. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109085 · Cited by 39 · see citing works
“While common variants and de novo mutations have been shown to play a role in a range of neurodevelopmental disorders, including hydrocephalus (Niemi et al., 2018; Short et al., 2018; Furey et al., 2018), this study implicates common variant-mediated regulation of tissue-specific gene expression as a potential driver…”
BackgroundLin, H. P., McBride, K. L., Garg, V., & Zhao, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.630069 · Cited by 33 · see citing works
Clinical implementation of RNA sequencing for Mendelian disease diagnosticsPreprint
Yépez, V. A., Gušić, M., Kopajtich, R., Mertes, C., Smith, N. H., Alston, C. L., Ban, R., Beblo, S., Berutti, R., Blessing, H., et al. (2021) · medRxiv · doi:10.1101/2021.04.01.21254633 · Cited by 32 · see citing works
Shin, T., Song, J. H. T., Kosicki, M., Kenny, C. J., Beck, S. G., Kelley, L., Antony, I., Qian, X., Bonacina, J., Papandile, F., et al. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100609 · Cited by 32 · see citing works
“12 Consanguineous families, which are enriched for recessive contributions because of shared ancestry, have also proved powerful for identifying the contribution to ASD of non-coding regions, including inherited, homozygous deletions, which have not been detectable in non-consanguineous families.”
Classification of non-coding variants with high pathogenic impact
Moyon, L., Berthelot, C., Louis, A., Nguyen, N. T. T., & Crollius, H. R. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010191 · Cited by 32 · see citing works
Sánchez-Luquez, K., Carpena, M. X., Karam, S. D. M., & Tovo‐Rodrigues, L. (2022) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2022.108428 · Cited by 31 · see citing works
A primer to clinical genome sequencing
Priest, J. R. (2017) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000532 · Cited by 29 · see citing works
Recent genetic and functional insights in autism spectrum disorder
Nakanishi, M., Anderson, M. P., & Takumi, T. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000718 · Cited by 29 · see citing works
Whole genome sequencing of 45 Japanese patients with intellectual disability
Abe‐Hatano, C., Iida, A., Kosugi, S., Momozawa, Y., Terao, C. C., Ishikawa, K., Okubo, M., Hachiya, Y., Nishida, H., Nakamura, K., et al. (2021) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62138 · Cited by 29 · see citing works
“Recently, variants in noncoding regions have also been highlighted as ID causes (Devanna, van de Vorst, Pfundt, Gilissen, & Vernes, 2018; Niemi et al., 2018; Short et al., 2018; Smedley et al., 2016).”
BackgroundGerrard, D. T., Berry, A. A., Jennings, R. E., Birket, M. J., Zarrineh, P., Garstang, M. G., Withey, S., Short, P., Jiménez-Gancedo, S., Firbas, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17305-2 · Cited by 26 · see citing works
Self-citationComputational and experimental methods for classifying variants of unknown clinical significance.Preprint
Spielmann, M., & Kircher, M. (2022) · PubMed Central · doi:10.1101/mcs.a006196 · Cited by 28 · see citing works
“The Deciphering Developmental Disorders study and the U.K. 100,000-genomes project showed that ∼40% of all patients with developmental delay carry a pathogenic de novo mutation in their coding sequence (Short et al. 2018; 100,000 Genomes Project Pilot Investigators et al. 2021).”
BackgroundGenetic testing for unexplained perinatal disorders
Hays, T., & Wapner, R. J. (2021) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000999 · Cited by 27 · see citing works
Next-Generation Sequencing in Autism Spectrum DisorderPreprint
Sanders, S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026872 · Cited by 28 · see citing works
“What is clear is that larger cohorts ofWGS datawill be needed to define the noncoding contribution of de novo variants in ASD; a similar conclusion was reached in an analysis of de novovariants in conserved enhancers in developmental delay (Short et al. 2018).”
ResultSpecchia, V., Puricella, A., D’Attis, S., Massari, S., Giangrande, A., & Bozzetti, M. P. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00010 · Cited by 25 · see citing works
Colin, E., Duffourd, Y., Chevarin, M., Tisserant, É., Verdez, S., Paccaud, J., Bruel, A., Mau‐Them, F. T., Denommé‐Pichon, A., Thévenon, J., et al. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1021920 · Cited by 25 · see citing works
“In addition, rare variants located in noncoding regions, such as deep intronic or regulatory variants, may need additional lines of evidence to demonstrate their implication in human disease, as shown in individuals 12 and 13 (Short et al., 2018; Bodle et al., 2021; Bryen et al., 2021).”
BackgroundFatima, A., Hoeber, J., Schuster, J., Koshimizu, E., Maya‐González, C., Keren, B., Mignot, C., Akram, T., Ali, Z., Miyatake, S., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.02.015 · Cited by 24 · see citing works
Gardner, E. J., Sifrim, A., Lindsay, S., Prigmore, E., Rajan, D., Danecek, P., Gallone, G., Eberhardt, R. Y., Martin, H. C., Wright, C. F., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.09.010 · Cited by 24 · see citing works
Self-citationChawner, S. J. R. A., Evans, A., Wolstencroft, J., Chawner, S. J. R. A., Hall, J., van den Bree, M. B. M., Owen, M. J., Skuse, D., Raymond, F. L., Williams, N. M., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-022-02296-z · Cited by 24 · see citing works
Sanchis-Juan, A., Megy, K., Stephens, J., Armirola Ricaurte, C., Dewhurst, E., Low, K., French, C. E., Grozeva, D., Stirrups, K., Erwood, M., et al. (2023) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2023.07.007 · Cited by 24 · see citing works
- 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 · 2017: 6
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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