# Molecular mechanisms and genetic drivers of reciprocal genomic disorders

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $682,120

## Abstract

ABSTRACT
Reciprocal genomic disorders (RGDs) involve recurrent microdeletion and microduplicaton of identical genomic
segments. RGDs are mediated by non-allelic homologous recombination (NAHR) and are collectively among
the most common recurrent genetic causes of neurodevelopmental disorders (NDD) and congenital anomalies
in humans. Given that the impact of RGDs is usually early in development, these disorders disproportionately
affect children and often result in lifelong disabilities. Discovery of the genes the molecular consequences of
RGDs and the genes that underlie components of these disorders would therefore represent exceptionally high
priority targets for mechanistic studies and therapeutic targeting across a spectrum of Mendelian and complex
disorders. Our Preliminary Data suggest that an integrated in vitro and in vivo molecular and computational
genomics approach using cellular and animal modeling can identify molecular signatures associated with
RGDs and the genetic drivers of aberrant phenotypes and dysregulated networks. In these studies, we will
first define the gene expression profiles and cellular phenotypes associated with microdeletion and
microduplication of the 8-12 most prevalent RGD regions in neural derivatives from isogenic induced
pluripotent stem cell (iPSC) lines. We will accomplish this using a CRISPR/Cas9 genome editing approach we
recently developed that targets the flanking segmental duplications and mimics NAHR-mediated mechanisms
in humans (Aim 1). We will then seek the specific genes associated with RGD-associated phenotypes using
high-throughput driver gene screening in zebrafish (Aim 2) to evaluate all individual genes and pairwise
interactions within RGD regions. In Aim 3 we will then seek to validate these predicted drivers and determine
their impact in diverse neuronal lineages and across mouse tissues. These studies will thus follow a framework
our investigative team has previously used to identify genetic drivers of non-recurrent microdeletion syndromes
and several RGD regions, including 16p11.2 RGD, and apply innovative approaches and technologies to
enable us to conduct these studies at scale and compare signatures across RGDs. At their conclusion, tehse
analyses will define the molecular signatures of the most common RGDs in humans, the genes that drive
specific components of these signatures, their tissue specificity, and the capacity to rescue the strongest
signatures through dosage manipulation in vitro and in vivo.

## Key facts

- **NIH application ID:** 10425331
- **Project number:** 5R01HD096326-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MICHAEL E TALKOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $682,120
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425331

## Citation

> US National Institutes of Health, RePORTER application 10425331, Molecular mechanisms and genetic drivers of reciprocal genomic disorders (5R01HD096326-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10425331. Licensed CC0.

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