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Diagnostic yield and copy number variants findings in 219 adult patients with developmental and epileptic encephalopathy.

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Title: Diagnostic yield and copy number variants findings in 219 adult patients with developmental and epileptic encephalopathy.
Authors: Licchetta L; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Bruschi G; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Giangregorio T; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Stipa C; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy., Mannini E; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Minardi R; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy., Mostacci B; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy., Tontini V; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy., Pippucci T; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Bisulli F; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Magini P; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Source: Epilepsia [Epilepsia] 2026 Sep; Vol. 67 (9), pp. e141-e149. Date of Electronic Publication: 2026 Jul 04.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Blackwell Science Country of Publication: United States NLM ID: 2983306R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-1167 (Electronic) Linking ISSN: 00139580 NLM ISO Abbreviation: Epilepsia Subsets: MEDLINE
Imprint Name(s): Publication: Malden, MA : Blackwell Science
Original Publication: Copenhagen : Munskgaard
MeSH Terms: DNA Copy Number Variations*/genetics , Epilepsy*/genetics , Epilepsy*/diagnosis, Humans ; Female ; Adult ; Male ; Comparative Genomic Hybridization ; Young Adult ; Middle Aged ; Adolescent ; Polymorphism, Single Nucleotide ; Exome Sequencing
Abstract: In a clinical setting, exome sequencing (ES) with copy number variant (CNV) analysis is currently the most effective approach for developmental and epileptic encephalopathies (DEE). However, trio-based ES is often not feasible in adults, its costs remain prohibitive in certain health care settings, and computational tools for CNV calling still lack sufficient accuracy. Chromosomal microarray (CMA) is indicated as a first-tier test for CNV detection in patients with DEE, dysmorphisms, and comorbidities. We investigate the role of CNVs in the etiology of DEE in an adult cohort, to define the most appropriate diagnostic approach in this population. A total of 219 patients (male/female: 104/115) with undiagnosed DEE underwent array-based comparative genomic hybridization/single nucleotide polymorphism arrays as adults. Causative CNVs were identified in 18 patients (8.2%); 14 were deletions (mean size ≈ 2.96 Mb), and four were duplications/triplications (mean size ≈ 3.63 Mb). Thirteen were responsible for known deletion/microduplication syndromes, and four were deletions involving haploinsufficient genes associated with epilepsy/neurodevelopmental disorders. For one deletion, population evidence, reports with overlapping deletions, and clinical databases support a likely pathogenic role. The mean age at CMA diagnosis was 32.4 ± 13 years. An additional 46 patients (21%) then received a molecular diagnosis through alternative approaches. Despite a diagnostic delay of 24.2 ± 14.5 years, CMA enabled a genetic diagnosis in 8.2% of our adult DEE patients, especially in those with dysmorphisms. The diagnostic yield rises to 10.4% when excluding patients diagnosed using other methods. A total of 66.7% of solved cases had direct implications from the diagnosis, supporting the clinical utility of CNV analysis inclusion in the diagnostic workflow for adult patients with DEE.
(© 2026 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
References: Epilepsia. 2023 May;64(5):1368-1375. (PMID: 36808730)
Genet Med. 2020 Feb;22(2):245-257. (PMID: 31690835)
Mol Genet Genomic Med. 2018 Mar;6(2):186-199. (PMID: 29314763)
Eur J Med Genet. 2012 May;55(5):342-8. (PMID: 22342432)
Eur J Hum Genet. 2021 Aug;29(8):1235-1244. (PMID: 34092786)
Epilepsia. 2017 Apr;58(4):512-521. (PMID: 28276062)
JAMA Neurol. 2017 Nov 1;74(11):1301-1311. (PMID: 28846756)
Neuroscience. 2019 Oct 15;418:291-310. (PMID: 31487502)
Am J Hum Genet. 2011 Feb 11;88(2):138-49. (PMID: 21276947)
Pediatr Neurol. 2014 Nov;51(5):730-3. (PMID: 25193415)
Nat Rev Dis Primers. 2024 Sep 5;10(1):61. (PMID: 39237642)
Epilepsia. 2022 Feb;63(2):375-387. (PMID: 34893972)
Sci Prog. 2022 Oct-Dec;105(4):368504221131233. (PMID: 36217831)
Case Rep Genet. 2015;2015:876348. (PMID: 26075115)
Ann Neurol. 2011 Dec;70(6):974-85. (PMID: 22190369)
Mol Syndromol. 2018 Jul;9(4):175-181. (PMID: 30140195)
Clin Genet. 2019 Jan;95(1):95-111. (PMID: 29992546)
Epileptic Disord. 2022 Oct 1;24(5):765-786. (PMID: 35830287)
Epilepsia. 2026 Sep;67(9):e141-e149. (PMID: 42400436)
Genet Med. 2021 Aug;23(8):1492-1497. (PMID: 33911214)
Mov Disord. 2020 May;35(5):880-885. (PMID: 31922365)
Neurology. 2019 Jan 28;92(5):e418-e428. (PMID: 30610098)
Eur J Hum Genet. 2014 Jan;22(1):79-87. (PMID: 23695279)
Am J Med Genet A. 2013 Oct;161A(10):2634-40. (PMID: 23949945)
Seizure. 2017 Dec;53:86-93. (PMID: 29156220)
Grant Information: Ministero della Salute
Contributed Indexing: Keywords: SNP array; adults; array CGH; developmental and epileptic encephalopathies; microarray
Entry Date(s): Date Created: 20260704 Date Completed: 20260921 Latest Revision: 20260923
Update Code: 20260923
PubMed Central ID: PMC13592487
DOI: 10.1002/epi.70360
PMID: 42400436
Database: MEDLINE
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  Data: Diagnostic yield and copy number variants findings in 219 adult patients with developmental and epileptic encephalopathy.
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  Data: <searchLink fieldCode="AU" term="%22Licchetta+L%22">Licchetta L</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Bruschi+G%22">Bruschi G</searchLink>; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Giangregorio+T%22">Giangregorio T</searchLink>; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Stipa+C%22">Stipa C</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Mannini+E%22">Mannini E</searchLink>; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Minardi+R%22">Minardi R</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Mostacci+B%22">Mostacci B</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Tontini+V%22">Tontini V</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Pippucci+T%22">Pippucci T</searchLink>; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Bisulli+F%22">Bisulli F</searchLink>; IRCCS Istituto Delle Scienze Neurologiche di Bologna, full member of European Reference Network EpiCARE, Bologna, Italy.; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.<br /><searchLink fieldCode="AU" term="%22Magini+P%22">Magini P</searchLink>; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
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  Data: In a clinical setting, exome sequencing (ES) with copy number variant (CNV) analysis is currently the most effective approach for developmental and epileptic encephalopathies (DEE). However, trio-based ES is often not feasible in adults, its costs remain prohibitive in certain health care settings, and computational tools for CNV calling still lack sufficient accuracy. Chromosomal microarray (CMA) is indicated as a first-tier test for CNV detection in patients with DEE, dysmorphisms, and comorbidities. We investigate the role of CNVs in the etiology of DEE in an adult cohort, to define the most appropriate diagnostic approach in this population. A total of 219 patients (male/female: 104/115) with undiagnosed DEE underwent array-based comparative genomic hybridization/single nucleotide polymorphism arrays as adults. Causative CNVs were identified in 18 patients (8.2%); 14 were deletions (mean size ≈ 2.96 Mb), and four were duplications/triplications (mean size ≈ 3.63 Mb). Thirteen were responsible for known deletion/microduplication syndromes, and four were deletions involving haploinsufficient genes associated with epilepsy/neurodevelopmental disorders. For one deletion, population evidence, reports with overlapping deletions, and clinical databases support a likely pathogenic role. The mean age at CMA diagnosis was 32.4 ± 13 years. An additional 46 patients (21%) then received a molecular diagnosis through alternative approaches. Despite a diagnostic delay of 24.2 ± 14.5 years, CMA enabled a genetic diagnosis in 8.2% of our adult DEE patients, especially in those with dysmorphisms. The diagnostic yield rises to 10.4% when excluding patients diagnosed using other methods. A total of 66.7% of solved cases had direct implications from the diagnosis, supporting the clinical utility of CNV analysis inclusion in the diagnostic workflow for adult patients with DEE.<br /> (© 2026 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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  Data: Epilepsia. 2023 May;64(5):1368-1375. (PMID: <searchLink fieldCode="PM" term="%2236808730%22">36808730)</searchLink><br />Genet Med. 2020 Feb;22(2):245-257. (PMID: <searchLink fieldCode="PM" term="%2231690835%22">31690835)</searchLink><br />Mol Genet Genomic Med. 2018 Mar;6(2):186-199. (PMID: <searchLink fieldCode="PM" term="%2229314763%22">29314763)</searchLink><br />Eur J Med Genet. 2012 May;55(5):342-8. (PMID: <searchLink fieldCode="PM" term="%2222342432%22">22342432)</searchLink><br />Eur J Hum Genet. 2021 Aug;29(8):1235-1244. (PMID: <searchLink fieldCode="PM" term="%2234092786%22">34092786)</searchLink><br />Epilepsia. 2017 Apr;58(4):512-521. (PMID: <searchLink fieldCode="PM" term="%2228276062%22">28276062)</searchLink><br />JAMA Neurol. 2017 Nov 1;74(11):1301-1311. (PMID: <searchLink fieldCode="PM" term="%2228846756%22">28846756)</searchLink><br />Neuroscience. 2019 Oct 15;418:291-310. (PMID: <searchLink fieldCode="PM" term="%2231487502%22">31487502)</searchLink><br />Am J Hum Genet. 2011 Feb 11;88(2):138-49. (PMID: <searchLink fieldCode="PM" term="%2221276947%22">21276947)</searchLink><br />Pediatr Neurol. 2014 Nov;51(5):730-3. (PMID: <searchLink fieldCode="PM" term="%2225193415%22">25193415)</searchLink><br />Nat Rev Dis Primers. 2024 Sep 5;10(1):61. (PMID: <searchLink fieldCode="PM" term="%2239237642%22">39237642)</searchLink><br />Epilepsia. 2022 Feb;63(2):375-387. (PMID: <searchLink fieldCode="PM" term="%2234893972%22">34893972)</searchLink><br />Sci Prog. 2022 Oct-Dec;105(4):368504221131233. (PMID: <searchLink fieldCode="PM" term="%2236217831%22">36217831)</searchLink><br />Case Rep Genet. 2015;2015:876348. (PMID: <searchLink fieldCode="PM" term="%2226075115%22">26075115)</searchLink><br />Ann Neurol. 2011 Dec;70(6):974-85. (PMID: <searchLink fieldCode="PM" term="%2222190369%22">22190369)</searchLink><br />Mol Syndromol. 2018 Jul;9(4):175-181. (PMID: <searchLink fieldCode="PM" term="%2230140195%22">30140195)</searchLink><br />Clin Genet. 2019 Jan;95(1):95-111. (PMID: <searchLink fieldCode="PM" term="%2229992546%22">29992546)</searchLink><br />Epileptic Disord. 2022 Oct 1;24(5):765-786. (PMID: <searchLink fieldCode="PM" term="%2235830287%22">35830287)</searchLink><br />Epilepsia. 2026 Sep;67(9):e141-e149. (PMID: <searchLink fieldCode="PM" term="%2242400436%22">42400436)</searchLink><br />Genet Med. 2021 Aug;23(8):1492-1497. (PMID: <searchLink fieldCode="PM" term="%2233911214%22">33911214)</searchLink><br />Mov Disord. 2020 May;35(5):880-885. (PMID: <searchLink fieldCode="PM" term="%2231922365%22">31922365)</searchLink><br />Neurology. 2019 Jan 28;92(5):e418-e428. (PMID: <searchLink fieldCode="PM" term="%2230610098%22">30610098)</searchLink><br />Eur J Hum Genet. 2014 Jan;22(1):79-87. (PMID: <searchLink fieldCode="PM" term="%2223695279%22">23695279)</searchLink><br />Am J Med Genet A. 2013 Oct;161A(10):2634-40. (PMID: <searchLink fieldCode="PM" term="%2223949945%22">23949945)</searchLink><br />Seizure. 2017 Dec;53:86-93. (PMID: <searchLink fieldCode="PM" term="%2229156220%22">29156220)</searchLink>
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