{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:10:09Z","timestamp":1792714209759,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Complex neurodevelopmental disorders frequently reflect multiple neurologic symptoms which have shared molecular and network level mechanisms. Advances in genomic medicine have redefined these conditions as overlapping manifestations of brain circuit dysfunction with significant variability. This review examines the intersection of genomics, epilepsy, and neurodevelopment in complex neurodevelopmental disorders, emphasizing Dup15q syndrome as a model for understanding phenotypic variability. Methods: Authors conducted a clinical (non-systematic) review of the literature based on their experience with three patients with Dup15q who responded dramatically to neurostimulation. We synthesized current literature on genomic mechanisms underlying complex neurodevelopmental disorders focusing on Dup15q syndrome and its subtypes\u2014int15, idic15, and mosaic idic15. We integrated clinical, electrophysiologic, and molecular data to illustrate the spectrum of epilepsy phenotypes and their mechanistic underpinnings. Results: Dup15q syndrome demonstrates marked heterogeneity in epilepsy severity and seizure semiology, reflecting variable gene dosing effects, maternal imprinting of UBE3A, and altered GABAergic signaling. While idic15 is more strongly associated with refractory epilepsy and SUDEP, both idic15 and int15 subtypes show overlapping developmental and behavioral phenotypes. There is a well-known differential response to anti-seizure medications and emerging evidence for neurostimulation and precision medicine. Conclusion: Dup15q syndrome exemplifies the convergence of genomic, neurophysiologic, and developmental pathways in epilepsy. As genomic discovery expands, precision therapies will increasingly rely on collaborative research networks. Understanding the genomic architecture of Dup15q syndrome may inform personalized strategies for epilepsy treatment and prevention.<\/jats:p>","DOI":"10.3390\/genes17020163","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T11:09:22Z","timestamp":1769771362000},"page":"163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genomics of Complex Neurodevelopmental Disorders with Variable Epilepsy Phenotypes: A Clinical Review of Dup15q Syndrome"],"prefix":"10.3390","volume":"17","author":[{"given":"Drew","family":"Thodeson","sequence":"first","affiliation":[{"name":"MBBN Research, Omaha, NE 68106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3977-6831","authenticated-orcid":false,"given":"Trevor","family":"Lockard","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Nebraska, Omaha, NE 68114, USA"},{"name":"College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2717-6888","authenticated-orcid":false,"given":"Sookyong","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Nebraska, Omaha, NE 68114, USA"},{"name":"College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1001\/jamapsychiatry.2021.3815","article-title":"Neurodevelopmental Disorders Among Publicly or Privately Insured Children in the United States","volume":"79","author":"Straub","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/dmcn.13050","article-title":"Early intervention in neurodevelopmental disorders: Underlying neural mechanisms","volume":"58","author":"Cioni","year":"2016","journal-title":"Dev. 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