{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:05:48Z","timestamp":1792011948894,"version":"4.4.0"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["NIH 5U54NS108874"],"award-info":[{"award-number":["NIH 5U54NS108874"]}]},{"name":"National Institute of Health","award":["1R01NS112499-01A1"],"award-info":[{"award-number":["1R01NS112499-01A1"]}]},{"DOI":"10.13039\/100009712","name":"Dravet Syndrome Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009712","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001866","name":"Fonds National de la Recherche Luxembourg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001866","id-type":"DOI","asserted-by":"crossref"}]},{"name":"German Federal Ministry for Education and Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are \u2018variants of uncertain significance\u2019. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can \u2018tolerate\u2019 missense variants and which ones are \u2018essential\u2019 and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.<\/jats:p>\n               <jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &amp;gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.<\/jats:p>\n               <jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https:\/\/es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.<\/jats:p>","DOI":"10.1093\/brain\/awac381","type":"journal-article","created":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T21:26:43Z","timestamp":1665869203000},"page":"519-533","source":"Crossref","is-referenced-by-count":16,"title":["Delineation of functionally essential protein regions for 242 neurodevelopmental genes"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-4374","authenticated-orcid":false,"given":"Sumaiya","family":"Iqbal","sequence":"first","affiliation":[{"name":"The Center for the Development of Therapeutics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"},{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"},{"name":"Analytic and Translational Genetics Unit, Massachusetts General Hospital , 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-6903","authenticated-orcid":false,"given":"Andreas","family":"Brunklaus","sequence":"additional","affiliation":[{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children , Glasgow G12 8QQ , UK"},{"name":"School of Health and Wellbeing, College of Medical, Veterinary and Life Sciences , University of Glasgow, Glasgow G12 8QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Daly","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"},{"name":"Analytic and Translational Genetics Unit, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Institute for Molecular Medicine Finland (FIMM), Centre of Excellence in Complex Disease Genetics , University of Helsinki, 00100 Helsinki , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur J","family":"Campbell","sequence":"additional","affiliation":[{"name":"The Center for the Development of Therapeutics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"},{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4679-0557","authenticated-orcid":false,"given":"David","family":"Hoksza","sequence":"additional","affiliation":[{"name":"Department of Software Engineering, Faculty of Mathematics and Physics, Charles University , 110 00 Star\u00e9 M\u011bsto, Czechia , Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8698-3770","authenticated-orcid":false,"given":"Patrick","family":"May","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, 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