Study of Genome-Wide DNA Methylation Profile in a Large Cohort of Patients with 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome in humans. The clinical phenotype is variable among different patients, also when they come from the same family, suggesting that nongenetic factors may be implicated in the pathogenesis. Recently, a specific episignature was defined for patients affected with 22q11.2DS. However, it has not been yet clarified whether these changes may reflect the variability of the phenotype observed among different patients. The study is aimed at defining genome-wide DNA methylation profiling in a large cohort of patients, including 63 carrying a deletion on the 22q11.2 chromosome and 5 with clinical features of DGS in whom genetic analysis did not reveal any alteration on the chromosome 22 (DGS-like). Among patients with 22q11.2 deletion, 12 were identified through FISH, suggesting that the deletion includes the proximal region, but information on the extension of the deletion is not available. For the remaining 51 patients, 38 carried the typical A-D deletion, 3 carried an A-B deletion, 7 carried a C-D deletion, while 3 patients carried a deletion downstream the DGS region. The analysis included 20 familial cases from 8 kindred. By selecting the 160 previously published differentially methylated CpG probes (DMPs), we were able to distinguish a specific methylation profile in the group of 38 patients carrying the typical A-D deletion, in the 3 patients carrying the A-B deletion, and in those diagnosed with FISH. On the contrary, the 7 patients carrying the distal C-D deletion, the 3 patients carrying a deletion downstream the DGS region and the DGS-like clustered with the controls. When the analysis was extended to a larger number of DMPs, we observed a gradient among typical deletion, distal deletions, DGS-like, and controls. Interestingly, most of the DMPs were found in the DGS region on the non-deleted allele. Hierarchical clustering also revealed similarities among affected and unaffected members of the different families, suggesting that epigenetic modifications may be partially inherited. These data showed a gradient of DMPs among typical deletion, distal deletions, DGS-like, and controls. This may suggest a correlation between the severity of the clinical phenotype and the degree of DNA methylation.

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