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Copy\u2010number gains (CN gains) in 15q11\u2010q13, primarily consisting of a pseudo (iso\u2010)dicentric chromosome 15 [(i)dic(15)] or an interstitial duplication, are among the most frequent CNVs in NDD. The associated Dup15q syndrome is an early onset neurodevelopmental disorder characterized by global developmental delay, behavioral issues, and seizures with a variable onset and expression of symptoms. While a correlation between the number of 15q11\u2010q13 CN gains and symptom severity has been proposed, it fails to fully explain the wide phenotypic variability observed. We conducted a comprehensive systematic literature\u2010based analysis of the supernumerary (i)dic(15), generating the largest literature\u2010based cohort consisting of patient\u2010level genotype data for Dup15q syndrome to date. Our findings identified symmetric BP3:BP3 and asymmetric BP4:BP5 (i)dic(15) configurations as the most common (i)dic(15) formations, likely arising from distinct mechanisms and potentially driving characteristic genotype\u2013phenotype outcomes. Additionally, we identified a significant gap within the molecular characterization of (i)dic(15), particularly regarding information on nucleotide\u2010level breakpoints, genomic structure, and differentially imprinted genes, being important aspects for genotype\u2013phenotype predictions. Our findings provide critical insight into the molecular architecture of (i)dic(15), offering valuable implications for understanding pathomechanisms and guidance for future research into the molecular and clinical aspects of Dup15q syndrome.<\/jats:p>","DOI":"10.1002\/ajmg.a.64186","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T07:20:20Z","timestamp":1752304820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Genomic Architecture of Supernumerary (Iso\u2010)Dicentric Chromosomes in Dup15q Syndrome: Insight From a Systematic Literature\u2010Based Study"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4135-066X","authenticated-orcid":false,"given":"Sebastian","family":"Burkart","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5054-5741","authenticated-orcid":false,"given":"Markus","family":"Ries","sequence":"additional","affiliation":[{"name":"Heidelberg University, Medical Faculty University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Pediatric Neurology and Metabolic Medicine  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Romero","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Hospital Heidelberg  Heidelberg Germany"},{"name":"Dup15q e.V.  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