Detection of genomic deletions by single-nucleotide polymorphism array comparative genomic hybridization

The purpose of these investigations was to determine whether the Affymetrix GeneChip Mapping Array (SNP chip) could be utilized to detect and map breakpoints in patients with contiguous gene deletion syndromes. The Affymetrix SNP chip is a high-density oligonucleotide array that allows a standardized, parallel interrogation of thousands of SNPs across the entire genome (except for the Y chromosome). We applied SNP array CGH to patients with complex glycerol kinase deficiency and DiGeorge syndrome as a proof of principle that this technique can detect and map chromosome loss.; Infantile, or complex glycerol kinase deficiency (cGKD), is a contiguous gene deletion syndrome caused by a deletion of GK, along with its neighboring genes, DMD and/or NR0B1 (previously called DAX1). Patients with cGKD, present with glyceroluria and hyperglycerolemia in association with Duchenne muscular dystrophy and/or adrenal hypoplasia congenita (AHC) if NR0B1 is also deleted. Genomic DNAs from several cell lines from patients with cGKD were analyzed on the Affymetrix platform. Analysis of the array feature hybridization intensities enabled delineation of the patient deletions and, combined with sequencing, we mapped the exact patients' breakpoints.; DiGeorge syndrome is estimated to occur in 1:4000 births and is the most common contiguous gene deletion syndrome in humans. Deletions in the 22q11.2 DiGeorge syndrome chromosome region (DGCR) prevent proper neural crest migration resulting in thymic and parathyroid hypoplasia and heart outflow tract defects. Genomic DNA was isolated from three well-characterized cell lines from Coriell and from a DiGeorge syndrome patient's blood, and analyzed by SNP array CGH. We confirmed the deletion breakpoints in the three cell lines and identified the patient's deletion to be in the 22q11.2 DGCR. In all four cases we detected a single copy of genomic DNA in this region compared with two copies in normal individuals.; This study demonstrates the utility of the Affymetrix Mapping GeneChips for molecular cytogenetic analysis, beyond the SNP genotyping for which the arrays were initially designed. With 1% of live births (40,000 U.S. neonates annually) having cytogenetic disorders, we envision a significant need for such a platform for rapid, high-throughput, genomic analysis for molecular cytogenetics applications.