Copy Number Variations in del22q11.2 Syndrome

Abstract

RATIONALE: Del22q11.2 syndrome is usually due to a deletion involving the Tbx gene on chromosome 22, but not all patients have the typical deletion, and not all patients with the deletion have full expression of the disease. A whole-genome approach may be better to understand and diagnose the disorder. We evaluated the use of 500,000 SNP mapping arrays and representational oligonucleotide microarray analysis (ROMA) in the delineation of the 22q11.2 deletion and identification of additional copy number variations (CNVs) elsewhere in the del22 syndrome genomes.METHODS: We evaluated CNVs using very-high-density ROMA in five patients with del22 syndrome. Identification of CNVs and pathologic deletions was by a new normalization and segmentation procedure (which we refer to as vivaROMA) that expanded on existing methods to improve comparisons between different arrays.RESULTS: The 22q11.2 deletion is easily identified, and our results agreed with the results of clinical flouresence in situ hybridization studies in all five patients. In addition, both patients and controls had numerous other CNVs elsewhere in the genome, consistent with the findings of other groups investigating CNVs in normal genomes. Some deletions elsewhere in del22 syndrome genomes involve coding regions that could affect immune system function.CONCLUSIONS: Genetic diversity outside of the 22q11.2 region may affect the phenotype in del22q11.2 syndrome. Use of whole genome approaches to the study of this disorder could enable the identification of new genes and hypotheses about the origins of immune system dysfunction. RATIONALE: Del22q11.2 syndrome is usually due to a deletion involving the Tbx gene on chromosome 22, but not all patients have the typical deletion, and not all patients with the deletion have full expression of the disease. A whole-genome approach may be better to understand and diagnose the disorder. We evaluated the use of 500,000 SNP mapping arrays and representational oligonucleotide microarray analysis (ROMA) in the delineation of the 22q11.2 deletion and identification of additional copy number variations (CNVs) elsewhere in the del22 syndrome genomes. METHODS: We evaluated CNVs using very-high-density ROMA in five patients with del22 syndrome. Identification of CNVs and pathologic deletions was by a new normalization and segmentation procedure (which we refer to as vivaROMA) that expanded on existing methods to improve comparisons between different arrays. RESULTS: The 22q11.2 deletion is easily identified, and our results agreed with the results of clinical flouresence in situ hybridization studies in all five patients. In addition, both patients and controls had numerous other CNVs elsewhere in the genome, consistent with the findings of other groups investigating CNVs in normal genomes. Some deletions elsewhere in del22 syndrome genomes involve coding regions that could affect immune system function. CONCLUSIONS: Genetic diversity outside of the 22q11.2 region may affect the phenotype in del22q11.2 syndrome. Use of whole genome approaches to the study of this disorder could enable the identification of new genes and hypotheses about the origins of immune system dysfunction.