title: New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.
abstract: BACKGROUND
  Array-CGH (aCGH) is presently used into routine clinical practice for diagnosis of patients with intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). ACGH could detect small chromosomal imbalances, copy number variations (CNVs), and closely define their size and gene content. ACGH detects pathogenic imbalances in 14-20 % of patients with ID. The aims of this study were: to establish clinical clues potentially associated with pathogenic CNVs and to identify cytogenetic indicators to predict the pathogenicity of the variants of uncertain significance (VOUS) in a large cohort of paediatric patients.
  
  
  METHODS
  We enrolled 214 patients referred for either: ID, and/or ASD and/or MCA to genetic services at the Federico II University of Naples, Department of Translational Medicine. For each patient we collected clinical and imaging data. All the patients were tested with aCGH or as first-tier test or as part of a wider diagnostic work-up.
  
  
  RESULTS
  Pathologic data were detected in 65 individuals (30 %) and 46 CNVs revealed a known syndrome. The pathological CNVs were usually deletions showing the highest gene-dosage content. The positive family history for ID/ASD/MCA and ASD were good indicators for detecting pathological chromosomal rearrangements. Other clinical features as eyes anomalies, hearing loss, neurological signs, cutaneous dyscromia and endocrinological problems seem to be potential predictors of pathological CNVs. Among patients carrying VOUS we analyzed genetic features including CNVs size, presence of deletion or duplication, genic density, multiple CNVs, to clinical features. Higher gene density was found in patients affected by ID. This result suggest that higher gene content has more chances to include pathogenic gene involved and causing ID in these patients.
  
  
  CONCLUSIONS
  Our study suggest the use of aCGH as first-tier test in patients with neurdevelopmental phenotypes. The inferred results have been used for building a flow-chart to be applied for children with ID.
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
authors.forename: Gerarda
authors.initials: G
authors.lastname: Cappuccio
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vitiello
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casertano
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fontana
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Genesio
authors.affiliation: Preventive Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Bruzzese
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Virginia Maria
authors.initials: VM
authors.lastname: Ginocchio
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Mormile
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Nitsch
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy. daniela.melis@unina.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization / Q000379:methods*; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D055815:Young Adult
keywords: Copy number variant (CNV); Intellectual disability; Multiple congenital anomalies; Pathogenic CNV; aCGH