{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:27:35Z","timestamp":1787318855803,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: The development and standardization of genome-wide technologies able to carry out high-resolution, genomic analyses in a cost- and time-affordable way is increasing our knowledge regarding the molecular bases of complex diseases like autism spectrum disorder (ASD). ASD is a group of heterogeneous diseases with multifactorial origins. Genetic factors seem to be involved, albeit they remain still largely unknown. Here, we report the case of a child with a clinical suspicion of ASD investigated by using such a genomic high-resolution approach. Materials and Methods: Both array comparative genomic hybridization (aCGH) and exome sequencing were carried out on the family trio. aCGH was performed using the 4 \u00d7 180 K SurePrint G3 Human CGH Microarray, while the Human All Exon V7 targeted SureSelect XT HS panel was used for exome sequencing. Results: aCGH identified a paternally inherited duplication of chromosome 7 involving the CNTNAP2 gene, while 5 potentially clinically-relevant variants were identified by exome sequencing. Conclusions: Within the identified genomic alterations, the CNTNAP2 gene duplication may be related to the patient\u2019s phenotype. Indeed, this gene has already been associated with brain development and cognitive functions, including language. The paternal origin of the alteration cannot exclude an incomplete penetrance. Moreover, other genomic factors may act as phenotype modifiers combined with CNTNAP2 gene duplication. Thus, the case reported herein strongly reinforces the need to use extensive genomic analyses to shed light on the bases of complex diseases.<\/jats:p>","DOI":"10.3390\/medicina58040522","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T21:08:22Z","timestamp":1649365702000},"page":"522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Combined aCGH and Exome Sequencing Analysis Improves Autism Spectrum Disorders Diagnosis: A Case Report"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3936-7219","authenticated-orcid":false,"given":"Annaluisa","family":"Ranieri","sequence":"first","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iolanda","family":"Veneruso","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"La Monica","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pascale","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Pastore","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9273-3698","authenticated-orcid":false,"given":"Valeria","family":"D\u2019Argenio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"},{"name":"Department of Human Sciences and Quality of Life Promotion, San Raffaele Open University, Via Di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Lombardo","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-030-30402-7_1","article-title":"Overview and Introduction to Autism Spectrum Disorder (ASD)","volume":"24","author":"Styles","year":"2020","journal-title":"Adv. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s13353-018-0440-y","article-title":"Diagnostic Efficacy and New Variants in Isolated and Complex Autism Spectrum Disorder Using Molecular Karyotyping","volume":"59","author":"Rajar","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13353-018-00480-w","article-title":"Genetics and Epigenetics of Autism Spectrum Disorder\u2014Current Evidence in the Field","volume":"60","author":"Nowakowska","year":"2019","journal-title":"J. Appl. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41572-019-0138-4","article-title":"Autism Spectrum Disorder","volume":"6","author":"Lord","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10048-014-0394-0","article-title":"Identification of Risk Genes for Autism Spectrum Disorder through Copy Number Variation Analysis in Austrian Families","volume":"15","author":"Egger","year":"2014","journal-title":"Neurogenetics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/dmcn.12278","article-title":"The Genetic Landscape of Autism Spectrum Disorders","volume":"56","author":"Rosti","year":"2014","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1001\/jama.2014.4144","article-title":"The Familial Risk of Autism","volume":"311","author":"Sandin","year":"2014","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Brancaccio, M., Mennitti, C., Cesaro, A., Monda, E., D\u2019argenio, V., Casaburi, G., Mazzaccara, C., Ranieri, A., Fimiani, F., and Barretta, F. (2021). Multidisciplinary In-Depth Investigation in a Young Athlete Suffering from Syncope Caused by Myocardial Bridge. Diagnostics, 11.","DOI":"10.3390\/diagnostics11112144"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1260","DOI":"10.1002\/mgg3.1260","article-title":"Genetic Analysis Resolves Differential Diagnosis of a Familial Syndromic Dilated Cardiomyopathy: A New Case of Alstr\u00f6m Syndrome","volume":"8","author":"Lombardo","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nunziato, M., Starnone, F., Lombardo, B., Pensabene, M., Condello, C., Verdesca, F., Carlomagno, C., De Placido, S., Pastore, L., and Salvatore, F. (2017). Fast Detection of a BRCA2 Large Genomic Duplication by next Generation Sequencing as a Single Procedure: A Case Report. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112487"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13039-015-0120-0","article-title":"Phenotypic and Genetic Characterization of a Family Carrying Two Xq21.1-21.3 Interstitial Deletions Associated with Syndromic Hearing Loss","volume":"8","author":"Iossa","year":"2015","journal-title":"Mol. Cytogenet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/jth.12061","article-title":"Aberrant F8 Gene Intron 1 Inversion with Concomitant Duplication and Deletion in a Severe Hemophilia A Patient from Southern Italy","volume":"11","author":"Sanna","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E52","DOI":"10.1002\/ajh.23913","article-title":"Identification of a Novel Variant of Epsilon-Gamma-Delta-Beta Thalassemia Highlights Limitations of next Generation Sequencing","volume":"90","author":"Zebisch","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1002\/ajmg.a.37770","article-title":"Mulibrey Nanism: Two Novel Mutations in a Child Identified by Array CGH and DNA Sequencing","volume":"170","author":"Mozzillo","year":"2016","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"602523","DOI":"10.3389\/fonc.2021.602523","article-title":"Case Report: Detection of a Novel Germline PALB2 Deletion in a Young Woman with Hereditary Breast Cancer: When the Patient\u2019s Phenotype History Doesn\u2019t Lie","volume":"11","author":"Nardelli","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e306","DOI":"10.1515\/cclm-2019-0137","article-title":"Molecular Diagnosis of MODY3 Permitted to Reveal a de Novo 12q24.31 Deletion and to Explain a Complex Phenotype in a Young Diabetic Patient","volume":"57","author":"Iafusco","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.gene.2015.01.044","article-title":"Oculo-Facio-Cardio-Dental (OFCD) Syndrome: The First Italian Case of BCOR and Co-Occurring OTC Gene Deletion","volume":"559","author":"Lombardo","year":"2015","journal-title":"Gene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1515\/cclm-2014-1255","article-title":"Two Novel Genomic Rearrangements Identified in Suicide Subjects Using A-CGH Array","volume":"53","author":"Lombardo","year":"2015","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e63","DOI":"10.1515\/cclm-2017-1106","article-title":"CGH Array for the Identification of a Compound Heterozygous Mutation in the CYP1B1 Gene in a Patient with Bilateral Anterior Segment Dysgenesis","volume":"57","author":"Lombardo","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e167","DOI":"10.1515\/cclm-2017-1090","article-title":"3q29 Microduplication in a Small Family with Complex Metabolic Phenotype from Southern Italy","volume":"56","author":"Vitale","year":"2018","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.gene.2013.10.074","article-title":"Identification of a Deletion in the NDUFS4 Gene Using Array-Comparative Genomic Hybridization in a Patient with Suspected Mitochondrial Respiratory Disease","volume":"535","author":"Lombardo","year":"2014","journal-title":"Gene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.gene.2013.11.051","article-title":"Microduplications in 22q11.2 and 8q22.1 Associated with Mild Mental Retardation and Generalized Overgrowth","volume":"536","author":"Tarsitano","year":"2014","journal-title":"Gene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ejhg.2013.100","article-title":"Shining a Light on CNTNAP2: Complex Functions to Complex Disorders","volume":"22","author":"Ho","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/sj.ejhg.5201824","article-title":"Disruption of the CNTNAP2 Gene in a t(7;15) Translocation Family without Symptoms of Gilles de La Tourette Syndrome","volume":"15","author":"Belloso","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Toma, C., Pierce, K.D., Shaw, A.D., Heath, A., Mitchell, P.B., Schofield, P.R., and Fullerton, J.M. (2018). Comprehensive Cross-Disorder Analyses of CNTNAP2 Suggest It Is Unlikely to Be a Primary Risk Gene for Psychiatric Disorders. PLoS Genet., 14.","DOI":"10.1101\/363846"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/YPG.0b013e32833a216f","article-title":"Association Analysis of CNTNAP2 Polymorphisms with Autism in the Chinese Han Population","volume":"20","author":"Xiaoping","year":"2010","journal-title":"Psychiatr. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2011.08.040","article-title":"Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits","volume":"147","author":"Abrahams","year":"2011","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4238\/gmr.15017422","article-title":"Single Nucleotide Polymorphisms in the CNTNAP2 Gene in Brazilian Patients with Autistic Spectrum Disorder","volume":"15","author":"Nascimento","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00401-017-1736-4","article-title":"Autism Spectrum Disorder: Neuropathology and Animal Models","volume":"134","author":"Varghese","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13052-021-01162-w","article-title":"Hyperkinetic Stereotyped Movements in a Boy with Biallelic CNTNAP2 Variants","volume":"47","author":"Scala","year":"2021","journal-title":"Ital. J. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/humu.23724","article-title":"Targeted Resequencing of 358 Candidate Genes for Autism Spectrum Disorder in a Chinese Cohort Reveals Diagnostic Potential and Genotype\u2013Phenotype Correlations","volume":"40","author":"Zhou","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/sj.mp.4002049","article-title":"CNTNAP2 Gene Dosage Variation Is Associated with Schizophrenia and Epilepsy","volume":"13","author":"Friedman","year":"2008","journal-title":"Mol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.3389\/fphys.2017.01080","article-title":"ACTN3: More than Just a Gene for Speed","volume":"8","author":"Pickering","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/7675","article-title":"A Common Nonsense Mutation Results in \u03b1-Actinin-3 Deficiency in the General Population","volume":"21","author":"North","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1002\/humu.23663","article-title":"Is Evolutionary Loss Our Gain? The Role of ACTN3 p.Arg577Ter (R577X) Genotype in Athletic Performance, Ageing, and Disease","volume":"39","author":"Houweling","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmg.2014.10.004","article-title":"Das Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism: Epidemiology, Metabolism and the Associated Diseases","volume":"58","author":"Liew","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sibarov, D.A., Boikov, S.I., Karelina, T.V., and Antonov, S.M. (2020). GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine. Biomolecules, 10.","DOI":"10.3390\/biom10101441"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/jnc.14775","article-title":"Role of GluN2A NMDA Receptor in Homocysteine-Induced Prostaglandin E2 Release from Neurons","volume":"150","author":"Rajagopal","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11154","DOI":"10.1074\/jbc.RA119.008820","article-title":"GluN2A-NMDA Receptor-Mediated Sustained Ca2+ Influx Leads to Homocysteine-Induced Neuronal Cell Death","volume":"294","author":"Deep","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1111\/jnc.14078","article-title":"Role of AMPA Receptors in Homocysteine-NMDA Receptor-Induced Crosstalk between ERK and P38 MAPK","volume":"142","author":"Poddar","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.neubiorev.2015.04.012","article-title":"The Association between Autism and Schizophrenia Spectrum Disorders: A Review of Eight Alternate Models of Co-Occurrence","volume":"55","author":"Chisholm","year":"2015","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/4\/522\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:50:01Z","timestamp":1760136601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/4\/522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,7]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["medicina58040522"],"URL":"https:\/\/doi.org\/10.3390\/medicina58040522","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,7]]}}}