As the Research Project of the Rose F. Kennedy IDDRC program, we propose to uncover the basis of intellectual disability (ID) in 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velo-cardio-facial syndrome). The 22q11.2DS is a congenital malformation disorder occurring in 1/4000 live births. Affected children suffer from cognitive impairment that ranges from mild to moderate and that frequently co-occurs with behavioral disorders. Most patients have a similar sized 3 million base pair (Mb) deletion, while some have nested proximal or distal deletions. The deletions occur sporadically by meiotic non-allelic homologous recombination events between blocks of low copy repeats that map to the 22q11.2 region. Most clinical findings in 22q11.2DS are relevant to the broader, general population but occur at a much higher frequency in affected individuals. For example, the prevalence of intellectual disability (ID) in the general population is 1- 3%, but virtually all children with 22q11DS have mild cognitive impairment and 50% have ID. Since the syndrome has a known genetic etiology, it is possible to identify the genes responsible for ID and explain the basis of phenotypic heterogeneity in patients. Once these are identified, mechanistic studies can contribute to our understanding of the molecular pathogenesis of ID, which will increase our knowledge of this common deficit. Our hypothesis is that haploinsufficiency of genes within the 22q11.2 region, including CRKL, encoding a cytoplasmic adaptor protein that functions in intracellular signaling, influences the severity of neurocognitive findings in patients with 22q11.2DS. We propose three specific aims to test this hypothesis.
In Aim 1, we will perform genetic studies to evaluate deletion size compared to phenotype, and analyze whole genome sequence on the remaining allele of 22q11.2 in 1,000 patients with the 3 Mb deletion from existing sequencing data. Further, we will examine patients with varying deletion sizes for neurocognitive and EEG findings.
In Aim 2, we will perform testing in mouse models to study the role of Crkl in brain development and function, and perform basic gene expression validation studies from discoveries found in Aim 1. In the pilot Aim 3, we will generate induced pluripotent stem cell lines from patients with varying deletion sizes and differentiate them to neurons to identify differential gene expression that will guide future genetic studies and drug screens. Overall, we believe this integrated approach will uncover new insights into the basis of ID in 22q11.2DS.
We are studying a relatively rare disorder with a known genetic etiology, termed 22q11.2 deletion syndrome (22q11.2DS). Patients with this syndrome have extremely variable phenotypes. While some have learning disabilities, half are considered in the mild to moderate intellectual disability (ID) range as quantified by IQ measures. The goal of this project is to identify the genetic and mechanistic basis of ID using the 22q11.2DS as a model.
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