Segmental duplication structural variation as the cause for the 22q11DS phenotypic variability

The 22q11 deletion syndrome (22q11DS), also known as the DiGeorge syndrome or Velo-Cardio-Facial syndrome, is the most common microdeletion syndrome, with a prevalence of 1 in 4000 births. The 22q11 deletion is caused by non-allelic homologous recombination between segmental duplications, causing a 3MB deletion in 90% of patients. Typical phenotypes include congenital heart defects, learning difficulties, characteristic facial features, and psychiatric anomalies. However, the presence and degrees of severity of most phenotypic features are highly variable across patients. The cause for this phenotypic variability remains largely unknown.

We demonstrated that a small part of the phenotypic variation can be explained by variants in genes on the remaining 22q11.2 allele. Current efforts focus on finding modifiers elsewhere in the genome. Here, we will inquire an alternative hypothesis that structural variation in the segmental duplicons flanking the 22q11DS region is a major determinant for the phenotypic variability, and more specific the psychiatric conditions. Due to the high complexity of the 8 large segmental duplicons averaging 250Kb, each composed of numerous segmental duplications, the exact nature of the low copy repeats and their variable structures has not yet been mapped. In this study we will map the haplotype structure, determine the rearrangement breakpoints and map the effect on gene expression.