# Molecular Dissection of the 22q11.2 Deletion Syndrome

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $537,004

## Abstract

Project Summary/Abstract
Numerous human diseases result from recurrent DNA rearrangements involving unstable genomic regions. They
are facilitated by the presence of region-specific low-copy repeats (LCRs) and are the result of nonallelic
homologous recombination (NAHR) between such paralogous genomic segments. The 22q11.2 region
undergoes a significant number of germline rearrangements. As such, it has been classified as one of the more
unstable regions of the human genome. The 22q11.2 deletion syndrome (22q11DS) is the most common
microdeletion disorder. It is associated with phenotypic and neuropsychiatric pathology, both of which are widely
variable. In most affected individuals, the deletion is de novo and is the result of NAHR mediated by four
chromosome22-specific low copy repeats (LCRA, -B, -C and -D) in 22q11. Their size and the presence of
numerous segments with near-identical sequence render these chromosome specific LCRs as substrates for
NAHR. Numerous genomic disorders, including the 22q11DS are the result of NAHR. LCR22s are extremely
difficult to reliably map and sequence because of their structural characteristics. Currently, an accurate reference
sequence for the region does not exist. Also, they are recalcitrant to short read sequencing such that the level
of their polymorphism and variability in the general population is unknown. However, optical mapping of the
region with Bionano Genomics' Saphyr technology overcomes this difficulty. Thus, 22q11.2 becomes a test case
for LCR delineation by optical mapping. Our preliminary optical mapping data suggests a complex organization
of duplicated 160kb modules within LCRA and LCRD, including copy number and orientation differences.
Further, a common inversion polymorphism within LCRD has been identified. Our preliminary data suggests that
this polymorphic inversion is less prevalent in African Americans (AAs), which may finally explain the relative
deficit of AAs in our CHOP-based 22q11DS cohort. We propose to employ innovative Bionano optical mapping
technology to determine the frequency of 22q11 LCR polymorphisms in the general population and explore the
role they play in facilitating rearrangements. The prevalence of the LCRD inversion in several different
populations (CEU, African, and African American subjects from the 1000 Genomes Project; local white and AA
22q11DS trios) will be determined. The LCR22-containing regions associated with 22q11DS will be examined in
these same populations to determine their structure and variation. Finally, we propose to analyze the breakpoints
of some typical and atypical 22q11.2 deletions and duplications guided by Bionano optical maps derived from
probands in the 22q11DS and duplication trios. By leveraging the increased sensitivity afforded by long single
molecule optical mapping on nanochannel arrays, this proposal will elucidate the previously unmapped structure
and variation of LCR22s and surrounding regions in greater detail. The data and ...

## Key facts

- **NIH application ID:** 10296523
- **Project number:** 2R01GM125757-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** BEVERLY S EMANUEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,004
- **Award type:** 2
- **Project period:** 2018-08-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296523

## Citation

> US National Institutes of Health, RePORTER application 10296523, Molecular Dissection of the 22q11.2 Deletion Syndrome (2R01GM125757-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10296523. Licensed CC0.

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