{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T10:31:57Z","timestamp":1774953117547,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,2,20]],"date-time":"2018-02-20T00:00:00Z","timestamp":1519084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008955","name":"Wilhelmina Kinderziekenhuis","doi-asserted-by":"publisher","award":["1614054"],"award-info":[{"award-number":["1614054"]}],"id":[{"id":"10.13039\/501100008955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001605","name":"Epilepsy Foundation","doi-asserted-by":"publisher","award":["2017\u201001"],"award-info":[{"award-number":["2017\u201001"]}],"id":[{"id":"10.13039\/100001605","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Phenotypes caused by de novo <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic> pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A protein (\u03b1\u2010subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist. A better prediction of disease severity is very much needed in daily practice to improve counseling, stressing the importance of identifying modifying factors in this patient group. We evaluated 128 participants with de novo, pathogenic <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic> variants to investigate whether mosaicism, caused by postzygotic mutation, is a major modifier in <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\u2010related epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mosaicism was investigated by reanalysis of the pathogenic <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic> variants using single molecule molecular inversion probes and next generation sequencing with high coverage. Allelic ratios of pathogenic variants were used to determine whether mosaicism was likely. Selected mosaic variants were confirmed by droplet digital polymerase chain reaction and sequencing of different tissues. Developmental outcome was classified based on available data on intelligence quotient and school functioning\/education.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mosaicism was present for 7.5% of de novo pathogenic <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic> variants in symptomatic patients. Mosaic participants were less severely affected than nonmosaic participants if only participants with truncating variants are considered (distribution of developmental outcome scores, Mann\u2010Whitney <jats:italic>U<\/jats:italic>,<jats:italic> P\u00a0<\/jats:italic>=\u00a0.023).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Postzygotic mutation is a common phenomenon in <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\u2010related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of <jats:italic><jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>1A<\/jats:italic>\u2010related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14021","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T19:40:50Z","timestamp":1519242050000},"page":"690-703","source":"Crossref","is-referenced-by-count":60,"title":["Mosaicism of de novo pathogenic <i><scp>SCN<\/scp>1A<\/i> variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-9224","authenticated-orcid":false,"given":"Iris M.","family":"de Lange","sequence":"first","affiliation":[{"name":"Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco J.","family":"Koudijs","sequence":"additional","affiliation":[{"name":"Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"van 't Slot","sequence":"additional","affiliation":[{"name":"Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boudewijn","family":"Gunning","sequence":"additional","affiliation":[{"name":"The Epilepsy Institutes of the Netherlands Foundation (SEIN)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja C. 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