Search for genetic modifiers for congenital heart disease in the 22q11.2 Deletion Syndrome

Abstract

The 22q11.2 deletion syndrome is characterized by great clinical heterogeneity among patients, and this heterogeneity does not seem to be related to the classes of more frequent deletion sizes (3 Mb, 1.5 Mb and atypical deletions). Thus, although the dose-sensitive genes mapped in the deleted region are important candidates for the phenotype, it has been suggested that more complex molecular mechanisms are involved in the 22q11.2 deletion syndrome. In addition to the genes of the 22q11.2 region, genetic modifiers, present in other regions of the genome, can directly influence the observed phenotypes. These modifiers are still poorly understood, however the contribution of CNVs (Copy Number Variation) and Single Nucleotide Polymorphisms (SNPs) in different regions of the genome is suggested. Thus, the present project proposes the study of CNVs and SNPs that act as modifiers for the congenital heart malformations present in the syndrome. To do so, the SNP-array data of 22q11.2 deletion patients will be explored with bioinformatic approaches and in silico tools. Polygenic risk score and biological pathway enrichment analyzes will be applied to identify variants that confer greater risk for cardiac phenotypes. This study will be important for a better understanding of the role of genetic modifiers involved in the expressivity of cardiac alterations in the 22q11.2 deletion syndrome. (AU)