Abstract
BackgroundArray-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.MethodsWe 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.ResultsPathologic 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13052-016-0246-7) contains supplementary material, which is available to authorized users.
Highlights
Array-CGH is presently used into routine clinical practice for diagnosis of patients with intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD)
The chromosomal imbalances detected by aCGH are defined copy number variations (CNVs) that are referred as: microdeletions and microduplications of clear clinical relevance or pathogenic, variants of uncertain significance (VOUS) and benign polymorphisms [6,7,8]
Brain Magnetic Resonance Imaging (MRI) findings have to be considered of contributory value but not essential in defining a genetic diagnosis or in the assessment of children with ID
Summary
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). The chromosomal imbalances detected by aCGH are defined copy number variations (CNVs) that are referred as: microdeletions and microduplications of clear clinical relevance or pathogenic, variants of uncertain significance (VOUS) and benign polymorphisms [6,7,8]. The advances in molecular methodology of aCGH technology, along with its broader application, facilitated the detection of novel pathogenic CNVs. The significance of many VOUS still remains uncertain causing serious problems in defining their contribution in patients affected by ID, MCA and ASD [9,10,11,12,13]
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