Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2.

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome.

Development of a high-density pericentromeric region BAC clone set for the detection and characterization of small supernumerary marker chromosomes by array CGH.

PURPOSE: Small supernumerary marker chromosomes are centric chromosomal segments that, by definition, cannot be characterized unambiguously by conventional chromosome banding. Marker chromosomes are of particular interest in clinical cytogenetics because they are nearly 10 times more frequent in individuals with mental retardation (0.426%) than in the normal population (0.043%). However, they are often found in only a small percentage of cells, making them difficult to detect and characterize in a diagnostic setting. We designed, constructed, and employed a bacterial artificial chromosome (BAC)-based microarray to demonstrate the utility of array-based comparative genomic hybridization (array CGH) for detecting and characterizing marker chromosomes in clinical diagnostic specimens. METHODS: We constructed a high-density microarray using 974 BAC clones that were mapped by fluorescence in situ hybridization and cover approximately 5 Mb of the most proximal unique sequence adjacent to the centromere on all 43 unique pericentromeric regions of the human genome (excluding the acrocentric short arms). This array was used to further characterize 20 previously identified marker chromosomes that were originally found with either conventional chromosome analysis or a targeted microarray. RESULTS: The enhanced coverage of this pericentromeric array not only identified the chromosomal origin of each marker in 15 cases, it also distinguished between the involvement of the short arm and/or the long arm of each chromosome, defined the sizes of many of the markers, and revealed complex rearrangements or multiple markers in single individuals. However, in five cases, the markers could not be identified by this assay, most likely because of very low levels of mosaicism and/or their small size and lack of detectable euchromatin. The expanded coverage of the pericentromeric regions represented on the array was adequate to refine the breakpoints in two-thirds of all cases in which a marker chromosome was identified by this assay. CONCLUSIONS: This study demonstrates the utility of array CGH in the detection and characterization of mosaic marker chromosomes. Because approximately one-third of the markers characterized in this study involved more unique sequence than that represented on this array, additional pericentromeric coverage may be even more valuable. We anticipate that this will allow detailed characterization of small supernumerary marker chromosomes that will greatly facilitate phenotype/genotype correlations and play a valuable role in the diagnosis and medical management of both pre- and postnatal cases in which marker chromosomes have been identified.