Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples.

High-resolution array comparative genomic hybridization (aCGH) is a powerful molecular cytogenetic tool that is being adopted for diagnostic evaluation of genomic imbalances and study disease mechanisms and pathogenesis. We report on the design and use, of a custom whole-genome oligonucleotide-based array (called KaryoArray®v3.0; Agilent-based 8 × 60 K) for diagnostic setting, which was able to detect new and unexpected rearrangements in 11/63 (~17.5%) of previous known pathological cases associated with known genetic disorders, and in the second step it identified at least one causal genomic imbalance responsible of the phenotype in ~20% of patients with psychomotor development delay and/or intellectual disability. To validate the array, first; we blindly tested 120 samples; 63 genomic imbalances that had previously been detected by karyotyping, FISH and/or MLPA, and 57 sex-matched control samples from healthy individuals; secondly a prospective study of 540 patients with intellectual disabilities, autism spectrum disorder and multiple congenital anomalies were evaluated to confirm the utility of the tool. These data indicate that implementation of array technologies as the first-tier test may reveal that additional genomic imbalances could co-exist in patients with trisomies and classical del/dup syndromes, suggesting that aCGH may also be indicated in these individuals, at least when phenotype does not match completely with genotype.

A parallel study of different array-CGH platforms in a set of Spanish patients with developmental delay and intellectual disability.

Developmental delay and intellectual disability, which occur in 1-3% of the population, account for a large number of the cases regularly seen in genetic units. Chromosomal microarray analysis has been shown to be a valuable clinical diagnostic assay and it should be the first-tier clinical diagnostic test for individuals with these conditions. However and due to several difficulties such as the platform resolution, the cost, and the inexperience with genomic data bases, the implementation of this test in many cytogenetic laboratories has been delayed. In an attempt to provide more insights of the benefits derived by using the chromosomal microarray analysis, this study presents the experience of two clinical centers using three different microarray platforms. The results obtained using a custom microarray (KaryoArray®) and two different commercial medium- and high-resolution whole-genome oligonucleotide microarrays have been compared. An overall diagnostic yield of around 15% has been obtained. However, the custom microarray platform has been shown to be more convenient for a clinical setting, since it allows the detection of more pathogenic copy number variants and less common variants.

Macrocephaly-cutis marmorata telangiectatica congenita: report of six new patients and a review.

We report on six additional patients with macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC; MIM 602501) and review the literature. This syndrome is a multiple congenital anomalies/mental retardation and overgrowth disorder comprising macrocephaly, cutis marmorata, vascular marks of lip and/or philtrum, syndactyly, hemihypertrophy, CNS anomalies, and developmental delay. Based on the findings in our 6 patients and on 69 patients previously reported we listed the very frequent (observed in >75%), frequent (25-75%), and less frequent (>25%) components of the syndrome.