Charting the genomic sequence of the 22q11 low copy repeats by cross-platform sequencing to unravel the causes of the phenotypic variability of the 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by non-allelic homologous recombination events. With an estimated incidence of 1 in 4000 live births, the 22q11.2 deletion syndrome is the most common chromosomal microdeletion disorder in humans. The mechanism behind this disorder involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region. Standard clinical testing can detect the 22q11.2DS both prenatally and postnatally. However, phenotypic features are never fully penetrant and the variability of symptoms remains largely unexplained. This has been identified as a crucial knowledge gap by researchers, clinicians, and families. The discovery of interindividual hypervariability in the LCR22s could provide a genetic explanation for (part of) the phenotypic variability, including the neuropsychiatric anomalies. To study the LCR22 variability in large numbers of patients and to identify the transcriptional and phenotypic consequences novel tools need to be developed. We will develop a targeted assembler and structural variation detector enabling cross-platform data integration to enable de novo assembly of the 22q11 LCR22 region and, by extension, other complex regions. In addition, we will provide both quantitative and qualitative transcriptome maps of the LCR22. Those new tools will allow us to unravel the contribution of LCR22 variability to the phenotypic variation.

Keywords:22q11 deletion syndrome, De novo assembly, low copy repeats

Disciplines:Analysis of next-generation sequence data, Computational transcriptomics and epigenomics, Development of bioinformatics software, tools and databases, Bioinformatics of disease