{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:12:29Z","timestamp":1790395949014,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,4,2]],"date-time":"2022-04-02T00:00:00Z","timestamp":1648857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00MH117165"],"award-info":[{"award-number":["R00MH117165"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50HD103525"],"award-info":[{"award-number":["P50HD103525"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Currently, protein\u2010coding de novo variants and large copy number variants have been identified as important for ~30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long\u2010read sequencing was applied to a family with autism, epileptic encephalopathy, cognitive impairment, and mild dysmorphic features (two affected female siblings, unaffected parents, and one unaffected male sibling) with no known clinical variant. From our long\u2010read sequencing data, a de novo missense variant in the\n                    <jats:italic>KCNC2<\/jats:italic>\n                    gene (encodes Kv3.2) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment revealed the variant was not in controls, highly conserved, and predicted damaging. This specific missense variant (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long\u2010lasting open state. Seven additional missense variants have been identified in other individuals with neurodevelopmental disorders (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a01.03\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ).\n                    <jats:italic>KCNC2<\/jats:italic>\n                    is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long\u2010read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.62743","type":"journal-article","created":{"date-parts":[[2022,4,2]],"date-time":"2022-04-02T05:05:22Z","timestamp":1648875922000},"page":"2071-2081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Germline mosaicism of a missense variant in\n                    <scp>\n                      <i>KCNC2<\/i>\n                    <\/scp>\n                    in a multiplex family with autism and epilepsy characterized by long\u2010read sequencing"],"prefix":"10.1002","volume":"188","author":[{"given":"Elvisa","family":"Mehinovic","sequence":"first","affiliation":[{"name":"Department of Genetics Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teddi","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Ekholm","sequence":"additional","affiliation":[{"name":"Pacific Biosciences  Menlo Park California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Wenger","sequence":"additional","affiliation":[{"name":"Pacific Biosciences  Menlo Park California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7422-1194","authenticated-orcid":false,"given":"William","family":"Rowell","sequence":"additional","affiliation":[{"name":"Pacific Biosciences  Menlo Park California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Grudo","sequence":"additional","affiliation":[{"name":"Pacific Biosciences  Menlo Park California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Grimwood","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology  Huntsville Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Korlach","sequence":"additional","affiliation":[{"name":"Pacific Biosciences  Menlo Park California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Gurnett","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8888-4186","authenticated-orcid":false,"given":"John N.","family":"Constantino","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-6477","authenticated-orcid":false,"given":"Tychele N.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Genetics Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,2]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"7.20","article-title":"Predicting functional effect of human missense mutations using PolyPhen\u20102","volume":"2013","author":"Adzhubei I.","year":"2013","journal-title":"Current Protocols in Human Genetics"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(05)80360-2"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat6576"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1094-136"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-01056-5"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0288-4"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0433-8"},{"key":"e_1_2_9_9_1","unstructured":"Garrison E. 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G.(2012).Haplotype\u2010based variant detection from short\u2010read sequencing. arXiv preprint arXiv:1207.3907 [q\u2010bio.GN]."},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3039"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4589"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1516376112"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13908"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.02.001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2832-5"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.229102"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3303"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.05.015"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","unstructured":"Martin M. 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