{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:58:11Z","timestamp":1790675891297,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["PRECISE.net"],"award-info":[{"award-number":["PRECISE.net"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MINT\u2010CS, #493665037"],"award-info":[{"award-number":["MINT\u2010CS, #493665037"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The mechanistic effects of genetic variants underlying genetic neurodevelopmental disorders (NDDs) are widely studied, but the contribution of external factors remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this cross\u2010sectional study using the Simons Searchlight population dataset, we examined caregiver\u2010reported environmental exposures and functional outcomes from 970 individuals with (67%) and without (33%) epilepsy across 93 NDDs. The primary outcome was adaptive function (Vineland\u20103) at last follow\u2010up, with quality of life (Quality of Life Inventory\u2013Disability) and autism symptoms (Social Communication Questionnaire\u2013Lifetime) as secondary analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to individuals with NDDs without epilepsy, individuals with epilepsy had lower adaptive function (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.001). On multivariable regression analysis, we found positive associations between socioeconomic factors and quality of life (parents' highest educational status: \u03b2\u2009=\u2009.014,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.013; annual household income: \u03b2\u2009=\u2009.007,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.021) and negative associations between treatment\u2010related factors and adaptive function (treatment with sodium channel blockers: \u03b2\u2009=\u2009\u2212.087,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20092.44\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ; hospitalizations: \u03b2\u2009=\u2009\u2212.055,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.65\u2009\u00d7\u200910\n                      <jats:sup>\u22127<\/jats:sup>\n                      ). These associations were mediated by epilepsy duration, etiology, and polytherapy. Results were consistent across sensitivity analyses but were not observed in individuals without epilepsy, suggesting epilepsy\u2010specific effects. Together, environmental exposures explained more variance in developmental outcomes than genetic etiology alone (additional\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200919.6%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.003). Importantly, the additional variance explained by environmental exposures was different across genes, ranging from ~15% (\n                      <jats:italic>SCN2A, SLC6A1<\/jats:italic>\n                      ) to &gt;30% (16p11.2 deletion), suggesting gene\u2010specific vulnerability. Overall, ~60% of variance in developmental outcomes remained unexplained, motivating further studies on genome and exposome influences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Our findings highlight genetic NDDs as genome\u2010informed yet exposure\u2010sensitive disorders. We found several external factors that both represent markers of epilepsy severity and may support early, genetically informed seizure management and careful stewardship of treatment exposures. Prospective, controlled studies are needed to disentangle the developmental effects of the underlying disease from treatment\u2010related factors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70268","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T17:36:56Z","timestamp":1784396216000},"page":"4870-4885","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Environmental and treatment\u2010related factors associated with developmental outcomes in genetic epilepsies"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1596-5599","authenticated-orcid":false,"given":"Christian M.","family":"Bo\u00dfelmann","sequence":"first","affiliation":[{"name":"Department for Neurology and Epileptology, Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE) Hertie Institute for Clinical Brain Research and Hertie Center of Neurology, University Hospital T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha N.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Center for Neuropsychological and Psychological Assessment Kennedy Krieger Institute  Baltimore Maryland USA"},{"name":"Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calliope","family":"Holingue","sequence":"additional","affiliation":[{"name":"Center for Autism Services, Science, and Innovation Kennedy Krieger Institute  Baltimore Maryland USA"},{"name":"Department of Mental Health Johns Hopkins Bloomberg School of Public Health  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Jimenez\u2010Gomez","sequence":"additional","affiliation":[{"name":"Department of Neurology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ganna","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland, Helsinki Institute of Life Science (HiLIFE), University of Helsinki  Helsinki Finland"},{"name":"Analytic and Translational Genetics Unit Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-846X","authenticated-orcid":false,"given":"M. Scott","family":"Perry","sequence":"additional","affiliation":[{"name":"Cook Children's Medical Center  Fort Worth Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5845-9610","authenticated-orcid":false,"given":"Ana","family":"Arenivas","sequence":"additional","affiliation":[{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Lal","sequence":"additional","affiliation":[{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Neurology McGovern Medical School, University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology and Harvard  Cambridge Massachusetts USA"},{"name":"Stanley Center for Psychiatric Research Broad Institute of Harvard and 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