New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.
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.


CONCLUSION
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.
['Cappuccio|Gerarda|G|', 'Vitiello|Francesco|F|', 'Casertano|Alberto|A|', 'Fontana|Paolo|P|', 'Genesio|Rita|R|', 'Bruzzese|Dario|D|', 'Ginocchio|Virginia Maria|VM|', 'Mormile|Angela|A|', 'Nitsch|Lucio|L|', 'Andria|Generoso|G|', 'Melis|Daniela|D|']
D000015:Abnormalities, Multiple D000293:Adolescent D000067877:Autism Spectrum Disorder D002648:Child D002675:Child, Preschool D002869:Chromosome Aberrations D055028:Comparative Genomic Hybridization D056915:DNA Copy Number Variations D005260:Female D006801:Humans D007223:Infant D008607:Intellectual Disability D008297:Male D055815:Young Adult
Intellectual disability aCGH Multiple congenital anomalies Pathogenic CNV Copy number variant (CNV)