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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 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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Cites
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 12,082
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
Self-citationIntegrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368
A general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183
GENCODE: The reference human genome annotation for The ENCODE Project
Harrow, J., Frankish, A., Gonzalez, J. M., Tapanari, E., Diekhans, M., Kokocinski, F., Aken, B. L., Barrell, D., Zadissa, A., Searle, S., et al. (2012) · Genome Research · doi:10.1101/gr.135350.111 · Cited by 4,585
Software for Computing and Annotating Genomic Ranges
Lawrence, M. F., Huber, W. K., Pagès, H., Aboyoun, P., Carlson, M. R. J., Gentleman, R. C., Morgan, M. T., & Carey, V. J. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003118 · Cited by 4,475
Hindorff, L. A., Sethupathy, P., Junkins, H. A., Ramos, E. M., Mehta, J. P., Collins, F. S., & Manolio, T. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903103106 · Cited by 4,013
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes
Siepel, A., Bejerano, G., Pedersen, J. S., Hinrichs, A. S., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L. W., Richards, S., et al. (2005) · Genome Research · doi:10.1101/gr.3715005 · Cited by 3,971
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., Reynolds, A. P., Sandstrom, R., Qu, H., Brody, J., et al. (2012) · Science · doi:10.1126/science.1222794 · Cited by 3,716
An atlas of active enhancers across human cell types and tissues
The FANTOM Consortium, Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., et al. (2014) · Nature · doi:10.1038/nature12787 · Cited by 2,550
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The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2019) · doi:10.1101/531210 · Cited by 1,662
A genomic mutational constraint map using variation in 76,156 human genomes
Chen, S., Francioli, L. C., Goodrich, J. K., Collins, R. L., Kanai, M., Wang, Q., Alföldi, J., Watts, N. A., Vittal, C., Gauthier, L. D., et al. (2024) · Nature · doi:10.1038/s41586-023-06045-0 · Cited by 1,727
A brief history of human disease genetics
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., et al. (2020) · Nature · doi:10.1038/s41586-019-1879-7 · Cited by 697
Self-citationExpansion of the Human Phenotype Ontology (HPO) knowledge base and resources
Köhler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. O. B., Danis, D., Gourdine, J.-P., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1105 · Cited by 677
Whole-genome sequencing of patients with rare diseases in a national health system
Turro, E., Astle, W. J., Megy, K., Gräf, S., Greene, D., Shamardina, O., Allen, H. L., Sanchis-Juan, A., Frontini, M., Thys, C., et al. (2020) · Nature · doi:10.1038/s41586-020-2434-2 · Cited by 554
Genetic Causes and Modifiers of Autism Spectrum Disorder
Rylaarsdam, L. E., & Guemez‐Gamboa, A. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00385 · Cited by 618
Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders
Sullivan, P. F., & Geschwind, D. H. (2019) · Cell · doi:10.1016/j.cell.2019.01.015 · Cited by 452
“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).”
ResultSelf-citationRegional missense constraint improves variant deleteriousness prediction
Samocha, K. E., Kosmicki, J. A., Karczewski, K. J., O’Donnell-Luria, A. H., Pierce-Hoffman, E., MacArthur, D. G., Neale, B. M., & Daly, M. J. (2017) · doi:10.1101/148353 · Cited by 351
A cross-disorder dosage sensitivity map of the human genome
Collins, R. L., Glessner, J., Porcu, E., Lepamets, M., Brandon, R. C., Lauricella, C., Han, L., Morley, T. J., Niestroj, L., Ulirsch, J. C., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.036 · Cited by 369
Self-citationGenome-wide de novo risk score implicates promoter variation in autism spectrum disorder
An, J.-Y., Lin, K., Zhu, L., Werling, D. M., Dong, S., Brand, H., Wang, H. Z., Zhao, X., Schwartz, G. B., Collins, R. L., et al. (2018) · Science · doi:10.1126/science.aat6576 · Cited by 316
“Similarly, we did not observe enrichment of mutations in ASD cases in the conserved noncoding elements described with targeted sequencing of 6239 families with severe developmental delay (12), although we note that our replication cohort is substantially smaller than the discovery cohort and of a different phenotype.”
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders
Niemi, M. E. K., Martin, H. C., Rice, D. L., Gallone, G., Gordon, S., Kelemen, M., McAloney, K., McRae, J., Radford, E. J., Yu, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0566-4 · Cited by 340
Self-citationCommon Disease Is More Complex Than Implied by the Core Gene Omnigenic Model
Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J., & Visscher, P. M. (2018) · Cell · doi:10.1016/j.cell.2018.05.051 · Cited by 309
“1574 Cell 173, June 14, 2018 dreds of genes may each be a core gene for different children presenting with severe childhood syndromes, and mutations in the same core gene are associated with extensive phenotypic heterogeneity (Jin et al., 2017; Short et al., 2018; Thomas and Berkovic, 2014).”
BackgroundRecommendations for clinical interpretation of variants found in non-coding regions of the genome
Ellingford, J. M., Ahn, J. W., Bagnall, R. D., Baralle, D., Barton, S., Campbell, C., Downes, K., Ellard, S., Duff‐Farrier, C. R. A., FitzPatrick, D. R., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01073-3 · Cited by 267
“It is important to note that sequence constraint and variant effect in non-coding regions has been shown to likely be basespecific rather than consistent across larger regions [17, 53].”
BackgroundSelf-citationWhole genome sequencing reveals that genetic conditions are frequent in intensively ill children
Disease, N. B., French, C. E., Next Generation Children Project, Delon, I., Dolling, H., Sanchis‐Juan, A., Shamardina, O., Mégy, K., Abbs, S. J., Austin, T., et al. (2019) · Intensive Care Medicine · doi:10.1007/s00134-019-05552-x · Cited by 260
Self-citationMendelian Gene Discovery: Fast and Furious with No End in Sight
Bamshad, M. J., Nickerson, D. A., & Chong, J. X. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.07.011 · Cited by 253
“26,27 Enrichment for non-coding SNVs in regulatory regions has been detected in, for example, developmental disorders 28 and autism, 29 but proving the pathogenicity for any one specific SNV is challenging because most are unique and alter non-overlapping bases.”
BackgroundWhole-genome sequencing of a sporadic primary immunodeficiency cohort
Thaventhiran, J. E. D., Allen, H. L., Burren, O. S., Rae, W. M., Greene, D. J., Staples, E., Zhang, Z., Farmery, J. H. R., Simeoni, I., Rivers, E., et al. (2020) · Nature · doi:10.1038/s41586-020-2265-1 · Cited by 242
Enhancer redundancy in development and disease
Kvon, E. Z., Waymack, R., Gad, M., & Wunderlich, Z. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00311-x · Cited by 247
Genetic Testing in Neurodevelopmental Disorders
Savatt, J. M., & Myers, S. M. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.526779 · Cited by 237
“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).”
BackgroundGenomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
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 224
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 219
“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 205
Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Whiffin, N., Karczewski, K. J., Zhang, X., Chothani, S. P., Smith, M. J., Evans, D. G., Roberts, A. M., Quaife, N. M., Schäfer, S., Rackham, O. J. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-10717-9 · Cited by 182
Karolak, J. A., Vincent, M., Deutsch, G. H., Gambin, T., Cogné, B., Pichon, O., Vetrini, F., Mefford, H. C., Dines, J. N., Golden‐Grant, K. L., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.12.010 · Cited by 164
Gazal, S., Loh, P.-R., Finucane, H. K., Ganna, A., Schoech, A., Sunyaev, S., & Price, A. L. (2018) · Nature Genetics · doi:10.1038/s41588-018-0231-8 · Cited by 154
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
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 140
Carrier screening for recessive disorders
Antonarakis, S. E. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0134-2 · Cited by 134
A deep catalogue of protein-coding variation in 983,578 individuals
Sun, K. Y., Bai, X., Chen, S., Bao, S., Zhang, C., Kapoor, M., Backman, J., Joseph, T., Maxwell, E., Mitra, G., et al. (2024) · Nature · doi:10.1038/s41586-024-07556-0 · Cited by 127
Rodin, R. E., Dou, Y., Kwon, M., Sherman, M. A., D’Gama, A. M., Doan, R. N., Rento, L. M., Girskis, K. M., Bohrson, C. L., Kim, S. N., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00765-6 · Cited by 135
NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements
Hirabayashi, S., Bhagat, S., Matsuki, Y., Takegami, Y., Uehata, T., Kanemaru, A., Itoh, M., Shirakawa, K., Takaori‐Kondo, A., Takeuchi, O., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0485-9 · Cited by 113
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 116
“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 117
“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 106
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 106
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
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 100
Lee, D. S. M., Ghanem, L. R., & Barash, Y. (2020) · Nature Communications · doi:10.1038/s41467-020-14404-y · Cited by 96
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 91
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 99
“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-Ríos, J., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01681-2 · Cited by 98
“…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 79
Alankarage, D., Ip, E., Szot, J. O., Munro, J. E., Blue, G. M., Harrison, K., Cuny, H., Enriquez, A., Troup, M., Humphreys, D. T., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0296-x · Cited by 82
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 90
Wang, W., Corominas, R., & Lin, G. N. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00258 · Cited by 70
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 71
Self-citationGenetic basis of mitochondrial diseases
Gušić, M., & Prokisch, H. (2021) · FEBS Letters · doi:10.1002/1873-3468.14068 · Cited by 79
“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
“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 75
“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
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
“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 71
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 77
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
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 74
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 75
Caron, B., Luo, Y., & Rausell, A. (2019) · Genome biology · doi:10.1186/s13059-019-1634-2 · Cited by 62
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., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-99747-2 · Cited by 64
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 63
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 70
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 73
Diagnosing rare diseases after the exomePreprint
Frésard, L., & Montgomery, S. B. (2018) · Molecular Case Studies · doi:10.1101/mcs.a003392 · Cited by 61
“…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
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 60
“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 59
“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 58
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
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 56
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
Zhai, Y., Zhang, Z., Shi, P., Martin, D. M., & Kong, X. (2021) · Human Mutation · doi:10.1002/humu.24222 · Cited by 52
“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 56
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 56
“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 50
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 49
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 46
“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 51
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 48
“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
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 44
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 43
Zug, R. (2022) · Biology Open · doi:10.1242/bio.058896 · Cited by 45
“…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 44
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
“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 35
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
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 33
“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 34
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 35
A primer to clinical genome sequencing
Priest, J. R. (2017) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000532 · Cited by 29
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 31
Whole genome sequencing of 45 Japanese patients with intellectual disability
Abe‐Hatano, C., Iida, A., Kosugi, S., Momozawa, Y., Terao, 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 30
“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 28
Self-citationComputational and experimental methods for classifying variants of unknown clinical significance.Preprint
Spielmann, M., & Kircher, M. (2022) · PubMed · doi:10.1101/mcs.a006196 · Cited by 28
“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 26
Next-Generation Sequencing in Autism Spectrum DisorderPreprint
Sanders, S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026872 · Cited by 30
“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 26
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 27
“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 25
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 25
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 25
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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