{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:34:10Z","timestamp":1760146450103,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health\u2014Current research IRCCS"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods: We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results: CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations (p = 0.019). Conclusions: The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling.<\/jats:p>","DOI":"10.3390\/genes15111441","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T09:24:13Z","timestamp":1730971453000},"page":"1441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Looks Can Be Deceiving: Diagnostic Power of Exome Sequencing in Debunking 15q11.2 Copy Number Variations"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6574-9608","authenticated-orcid":false,"given":"Camilla","family":"Meossi","sequence":"first","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2638-9910","authenticated-orcid":false,"given":"Alessia","family":"Carrer","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Milan, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-7028","authenticated-orcid":false,"given":"Claudia","family":"Ciaccio","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8111-563X","authenticated-orcid":false,"given":"Laura","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24100 Bergamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4601-2985","authenticated-orcid":false,"given":"Lidia","family":"Pezzani","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"},{"name":"Pediatric Unit, ASST Papa Giovanni XXIII, 24100 Bergamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa Maria","family":"Silipigni","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca L.","family":"Sciacca","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romano","family":"Tenconi","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Women and Children\u2019s Health, University of Padova, 35100 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6330-2562","authenticated-orcid":false,"given":"Silvia","family":"Esposito","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"De Laurentiis","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Pantaleoni","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Marchisio","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"},{"name":"Department of Health Sciences, University of Milan, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8625-3089","authenticated-orcid":false,"given":"Federica","family":"Natacci","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-9418","authenticated-orcid":false,"given":"Stefano","family":"D\u2019Arrigo","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Neurologico C. Besta, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24100 Bergamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3087-8514","authenticated-orcid":false,"given":"Donatella","family":"Milani","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1136\/jmg.2003.013813","article-title":"BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications","volume":"41","author":"Locke","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1086\/378816","article-title":"Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi\/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons","volume":"73","author":"Chai","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rafi, S.K., and Butler, M.G. (2020). The 15q11.2 BP1-BP2 Microdeletion (Burnside\u2013Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Disorders. Int. J. Mol. Sci., 21.","DOI":"10.37247\/PAMOLSCS.1.2020.17"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00439-011-0970-4","article-title":"Microdeletion\/microduplication of proximal 15q11.2 between BP1 and BP2: A susceptibility region for neurological dysfunction including developmental and language delay","volume":"130","author":"Burnside","year":"2011","journal-title":"Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.3390\/ijms16024068","article-title":"The 15q11.2 BP1-BP2 Microdeletion Syndrome: A Review","volume":"16","author":"Cox","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/jir.12382","article-title":"Clinical and genetic aspects of the 15q11.2 BP1\u2013BP2 microdeletion disorder","volume":"61","author":"Butler","year":"2017","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/gim.2012.164","article-title":"Estimates of penetrance for recurrent pathogenic copy-number variations","volume":"15","author":"Rosenfeld","year":"2013","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/jir.13038","article-title":"Clinical features and magnesium levels: Novel insights in 15q11.2 BP1\u2013BP2 copy number variants","volume":"67","author":"Meossi","year":"2023","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1002\/ajmg.a.40635","article-title":"Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy","volume":"176","author":"Pezzani","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000097433","article-title":"Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi\/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment","volume":"116","author":"Murthy","year":"2007","journal-title":"Cytogenet. Genome Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/brain\/awp262","article-title":"Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies","volume":"133","author":"Trucks","year":"2010","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ejmg.2015.01.002","article-title":"15q11.2 microdeletion (BP1\u2013BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients","volume":"58","author":"Vanlerberghe","year":"2015","journal-title":"Eur. J. Med Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1001\/jamapsychiatry.2019.3779","article-title":"Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition Supplemental content","volume":"77","author":"Kaufmann","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chu, F.-C., Shaw, S.W., Lee, C.-H., Lo, L.-M., Hsu, J.-J., and Hung, T.-H. (2021). Adverse Perinatal and Early Life Outcomes following 15q11.2 CNV Diagnosis. Genes, 12.","DOI":"10.3390\/genes12101480"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1159\/000477226","article-title":"Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test","volume":"8","author":"Monteiro","year":"2017","journal-title":"Mol. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41431-020-0626-8","article-title":"Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1\u2013BP2) deletion in the UK Biobank","volume":"28","author":"Williams","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41398-023-02358-w","article-title":"No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank","volume":"13","author":"Boen","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1002\/ajmg.a.37134","article-title":"Deletion of 15q11.2(BP1-BP2) region: Further evidence for lack of phenotypic specificity in a pediatric population","volume":"167","author":"Hashemi","year":"2015","journal-title":"Am. J. Med Genet. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1002\/ajmg.a.36554","article-title":"Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: Further delineation of an emerging syndrome","volume":"164","author":"Cafferkey","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Baldwin, I., Shafer, R.L., Hossain, W.A., Gunewardena, S., Veatch, O.J., Mosconi, M.W., and Butler, M.G. (2021). Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041660"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Davis, K.W., Serrano, M., Loddo, S., Robinson, C., Alesi, V., Dallapiccola, B., Novelli, A., and Butler, M. (2019). Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061459"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Maya, I., Perlman, S., Shohat, M., Kahana, S., Yacobson, S., Tenne, T., Agmon-Fishman, I., Mater, R.T., Salmon, B.L., and Halevy, R.S. (2020). Should We Report 15q11.2 BP1-BP2 Deletions and Duplications in the Prenatal Setting?. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082602"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Maver, A., \u010cuturilo, G., Kovanda, A., Mileti\u0107, A., and Peterlin, B. (2019). Rare missense TUBGCP5 gene variant in a patient with primary microcephaly. Eur. J. Med. Genet., 62.","DOI":"10.1016\/j.ejmg.2018.12.003"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rosina, E., Pezzani, L., Apuril, E., Pezzoli, L., Marchetti, D., Bellini, M., Lucca, C., Meossi, C., Massimello, M., and Mariani, M. (2023). Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study. Mol. Genet. Genom. Med., 12.","DOI":"10.1002\/mgg3.2316"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/s41436-019-0554-6","article-title":"Meta-analysis and multidisciplinary consensus statement: Exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders","volume":"21","author":"Srivastava","year":"2019","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/aur.1378","article-title":"Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2","volume":"7","author":"Chaste","year":"2014","journal-title":"Autism Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Genovese, A., and Butler, M.G. (2023). The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations. Genes, 14.","DOI":"10.3390\/genes14030677"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kreiman, B.L., and Boles, R.G. (2020). State of the Art of Genetic Testing for Patients With Autism: A Practical Guide for Clinicians. Semin. Pediatr. Neurol., 34.","DOI":"10.1016\/j.spen.2020.100804"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:28:14Z","timestamp":1760113694000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,7]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["genes15111441"],"URL":"https:\/\/doi.org\/10.3390\/genes15111441","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2024,11,7]]}}}