Identification of non-recurrent submicroscopic genome imbalances: the advantage of genome-wide microarrays over targeted approaches

Abstract

Genome-wide analysis of DNA copy-number changes using microarray-based technologies has enabled the detection of de novo cryptic chromosome imbalances in approximately 10% of individuals with mental retardation. So far, the majority of these submicroscopic microdeletions/duplications appear to be unique, hampering clinical interpretation and genetic counselling. We hypothesised that the genomic regions involved in these de novo submicroscopic aberrations would be candidates for recurrent copy-number changes in individuals with mental retardation. To test this hypothesis, we used multiplex ligationdependent probe amplification (MLPA) to screen for copy number changes at eight genomic candidate regions in a European cohort of 710 individuals with idiopathic mental retardation. By doing so, we failed to detect additional submicroscopic rearrangements, indicating that the anomalies tested are nonrecurrent in this cohort of patients. The break points flanking the candidate regions did not contain low copy repeats and/or sequence similarities, thus providing an explanation for its non-recurrent nature. On the basis of these data, we propose that the use of genome-wide microarrays is indicated when testing for copy-number changes in individuals with idiopathic mental retardation.

Educational Attainment: A Genome Wide Association Study in 9538 Australians

“…This region deserves future attention as it has been suggested to be involved in other brain phenotypes. This region contains the GAB2 gene, a candidate gene for Alzheimer's disease [32] and copy number variations in this region have also been linked with mental retardation [33].…”

Quantitative Real-Time Polymerase Chain Reaction for the Verification of Genomic Imbalances Detected by Microarray-Based Comparative Genomic Hybridization

“…M icroarray-based comparative genomic hybridization (aCGH) methodology is used to detect DNA copy number changes in the clinical setting (Baldwin et al, 2008;Bejjani and Shaffer, 2008;Koolen et al, 2008;Sharp, 2009). Abnormal or ambiguous aCGH results must be confirmed by a second method as required by the American College of Medical Genetics guidelines for aCGH analysis for constitutional cytogenetic abnormalities.…”

“…Advantages of FISH methods include the following: (1) FISH is in use in most clinical cytogenetic laboratories, (2) commercial FISH probes are available for common microdeletion=duplication syndromes, (3) FISH may identify mosaicism, which other methods have limited ability to resolve, and (4) FISH can provide information about chromosomal location and help clarify the mechanism for a deletion or duplication as long as the region is large enough for detection with FISH probes and metaphase chromosomes are available. Limitations of FISH methods include (1) limited availability of ready-to-use labeled FISH probes for genomic imbalances that are rare or private (Koolen et al, 2008), (2) the expense and challenge of setup and training of personnel to make and process home-brew FISH probes, (3) the expense of custom-designed FISH probes from commercial companies, (4) Bacterial artificial chromosome (BAC) clones purchased from public sources that are not specific or are annotated incorrectly (Perry et al, 2006;Redon et al, 2006), and (5) FISH probes, usually 100-150 kb, that are too large for the detection of small microdeletions or microduplications, for example, tandem duplications (Lee et al, 2007).…”

A de novo POU3F3 Deletion in a Boy with Intellectual Disability and Dysmorphic Features

“…The introduction of molecular karyotyping has also led to the identification of several new microdeletion and -duplication syndromes and also of new genes implicated in ID [Raymond, 2010;Vissers and Stankiewicz, 2012;Weise et al, 2012]. Besides recurrent deletion and duplication events, rarer copy number variations (CNVs) have also been described in ID [Koolen et al, 2008;Mikhail et al, 2011]. In this paper, we present a child with ID and dysmorphic features with a de novo deletion in chromosome band 2q12.1 affecting only 2 genes: POU3F3 (OMIM 602480) and MRPS9 (OMIM 611975).…”