Investigation of possible genetic modifiers in patients with the 22q11.2 deletion syndrome

Abstract

The 22q11.2 deletion syndrome is caused by the loss of DNA segments from a region of chromosome 22 that contains LCRs, or segmental duplications, with deletions of 3 Mb and 1.5 Mb of DNA being more frequent. The phenotypic expression of the syndrome is very heterogeneous, and does not seem to be related to the size of the deletions, being very variable even in patients with similar deletions and in patients of the same family. Although the dose-sensitive genes mapped in the deleted region are the main candidates for the phenotype, it is suggested that more complex mechanisms play a role in the syndrome phenotype. One of these is the presence of genetic modifiers in other regions of the genome, which can modify the severity of the phenotype established by the 22q11.2 deletion. These factors are not very well known, but it is suggested the participation of copy number variations (CNVs) and single nucleotide variants (SNVs) located in several regions of the genome. Therefore, this work aims to evaluate the heritability of CNVs and their contribution as a phenotype modifier in trios (patient, father and mother). In addition, it is intended to validate a variant previously identified by our research group, located in the JAM3 gene, related to the syndrome's cardiac phenotype. The results obtained will allow a greater understanding of the role of genetic modifiers in the phenotypic variability of the 22q11.2 deletion syndrome.