# Neural mechanisms of 3q29 deletion syndrome

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $67,446

## Abstract

PROJECT SUMMARY: Neurodevelopmental disorders such as autism and schizophrenia are known to have a
strong hereditary component but the genes and molecular determinants driving clinical phenotypes are not
understood. Recurrent genomic copy number variants (CNVs) have emerged as important, highly-penetrant
risk factors for these disorders. 3q29 deletion is one such CNV that results in the loss of one copy of 21
protein-coding genes, is strongly associated with autism, and is estimated to have the highest odds ratio of any
genetic variant linked to schizophrenia at >40.
 Phenotypically, the available evidence suggests that 3q29 deletion may compromise brain development.
Clinical case reports have described microcephaly and two independent mouse models of 3q29 deletion have
reduced brain weight. Alterations in brain growth are relatively common in idiopathic and CNV-associated
neurodevelopmental disorders and it has been hypothesized that dysregulated proliferation and maturation of
neural progenitor cells (NPCs) may underlie this phenomenon. Here, we propose to rigorously test the
proliferation of NPCs differentiated from 3q29 deletion study participant and isogenic induced pluripotent stem
cell (iPSC) lines by ELISA, immunofluorescence, and multiparametric flow cytometry. Furthermore, we will
generate both dorsal and ventral forebrain 3D organoids to assess the proliferation and differentiation of both
glutamatergic and GABAergic progenitors.
 In addition, we will narrow the list of potential phenotypic driver genes through transcriptomic studies of
human iPSC-derived NPCs and forebrain neurons. No single gene within the 3q29 deletion locus is currently
associated with autism or schizophrenia prompting the hypothesis that haploinsufficiency of multiple genes
within the interval contribute to risk for neurodevelopmental disorders. Indeed, preliminary weighted co-
expression network analysis indicates that the 21 protein-coding 3q29 deletion genes congregate in 7 co-
expression modules implying that multiple 3q29 genes participate in overlapping biological pathways. We will
conduct RNA-seq on NPCs and FACS-isolated neurons to identify differentially-expressed genes in human
3q29 deletion neural cells. We will then re-introduce candidate 3q29 driver genes to NPCs and neurons and
determine which 3q29 genes are responsible for dysregulation of downstream targets.
 The genetic and emerging phenotypic evidence strongly suggests that the 3q29 deletion is a high-priority
target for mechanistic investigation. The Emory 3q29 Project has generated 12 iPSC lines from 3q29 deletion
carriers along with age, sex, and race/ethnicity-matched controls. The tools are in place to rigorously
investigate cellular and molecular alterations attributable to this high-risk variant. These findings will advance
our understanding of this disorder and will be an important step toward understanding the genetic and
molecular drivers of neurodevelopmental disorders more broadly.

## Key facts

- **NIH application ID:** 10067027
- **Project number:** 1F32MH124273-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ryan Herndon Purcell
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 1
- **Project period:** 2020-07-28 → 2022-07-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067027

## Citation

> US National Institutes of Health, RePORTER application 10067027, Neural mechanisms of 3q29 deletion syndrome (1F32MH124273-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10067027. Licensed CC0.

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