# Molecular Dissection of the 22q11.2 Deletion Syndrome

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $124,000

## Abstract

Project Summary:
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 and has been classified as one of the most
unstable regions of the human genome. Thus, the 22q11.2 deletion syndrome (22q11.2DS) 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 22q11.2. Their size and the presence
of numerous segments with near-identical sequence render these chromosome specific LCRs as substrates
for 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 and long 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 has overcome this difficulty. Our 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
and other polymorphisms are less prevalent in African Americans (AAs), which may finally explain the relative
deficit of AAs in our CHOP-based 22q11.2DS cohort. Our funded R01 proposed 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) is being determined. The LCR22-containing regions associated with 22q11.2DS is
being examined in these populations to determine their structure and variation. Hence, by leveraging the
increased sensitivity afforded by long single molecule optical mapping on nanochannel arrays, this proposal is
elucidating the previously unmapped structure and variation of LCR22s and surrounding regions in detail. The
data and maps generated herein will provide us with a roadmap to gain access to many other difficult to map
and sequence genomic regions and other genomic disorders. However, our Generation 1 Saphyr System is
being phased out of production by Bionano Genomics, Thus, to continue this work, we need to trade in our
Generation 1 Saphyr system for a Gen...

## Key facts

- **NIH application ID:** 11100054
- **Project number:** 3R01GM125757-06S1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** BEVERLY S EMANUEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $124,000
- **Award type:** 3
- **Project period:** 2018-08-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100054

## Citation

> US National Institutes of Health, RePORTER application 11100054, Molecular Dissection of the 22q11.2 Deletion Syndrome (3R01GM125757-06S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/11100054. Licensed CC0.

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