Abstract
BackgroundAproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects.ResultsKnown genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%).ConclusionThis tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.
Highlights
5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome
Validation of the X-chromosome bacterial artificial chromosomes (BACs) array Sensitivity and specificity of the X-array to detect copy number changes were tested with DNA from four patients with known cytogenetic aberrations on the X chromosome
Copy number variations were observed in 26 patients (48%) and in 8 patients (14.8%), we identified imbalances probably causative of the phenotype observed in the patients
Summary
5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. Other copy number variations are present as polymorphisms in the general population without apparent relation to disease [7,8,9,10] Several of these cryptic chromosomal rearrangements occur in regions flanked by segmental duplications or low-copy repeats and likely result from non-allelic homologous recombination between different copies of these repeats [11]
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