# Project:  Genetic basis of intellectual disability in 22q11.2 deletion syndrome

> **NIH NIH U54** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $200,400

## Abstract

ABSTRACT 
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.

## Key facts

- **NIH application ID:** 9999355
- **Project number:** 5U54HD090260-06
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** BERNICE E MORROW
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,400
- **Award type:** 5
- **Project period:** 2016-09-22 → 2021-07-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999355

## Citation

> US National Institutes of Health, RePORTER application 9999355, Project:  Genetic basis of intellectual disability in 22q11.2 deletion syndrome (5U54HD090260-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999355. Licensed CC0.

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