Mapping the role of the low copy repeats in the phenotypic variability of the 22q11 Deletion Syndrome

The 22q11 deletion syndrome (22q11DS) is the most common
genomic disorder, with a prevalence of 1 in 3000 births. The reason
for this high incidence remains an enigma. The presence and
degrees of severity of most phenotypic features are highly variable
across patients and it remains unknown why some patients acquire
neuropsychiatric features and others do not. The deletion is caused
by non-allelic homologous recombination, typically causing a 3MB
deletion in 90% of patients. We demonstrated human specific
expansion and hypervariability of the low copy repeats (LCR) causing
the rearrangement with sizes ranging from 200kb to over 2.5Mb.
Since duplications in the genome are drivers of evolution and genes
in other LCRs have been shown to modulate brain development, we
hypothesize this variation could be an important determinant for the
22q11DS phenotypic variability and especially the neuropsychiatric
features. Using CRISPR/Cas9 editing, we will engineer human
embryonic stem cell lines to remove individual LCRs, determine the
effect on gene expression and map their differentiation potential into
neurons. We will map the haplotype structure, determine the
rearrangement breakpoints and map the effect on gene expression in
22q11DS patients to unravel the role of the LCRs in both the
mechanism causing and the phenotypic variation affecting 22q11DS.