# Cellular Basis for Genetic Susceptibility to Neurodevelopmental Disorders

> **NIH NIH R21** · PENNSYLVANIA STATE UNIVERSITY, THE · 2021 · $428,267

## Abstract

Project Summary
In contrast to syndromic CNVs such as the 17p11.2 deletion in Smith-Magenis syndrome, which mostly occur
de novo and are highly penetrant, more recent studies have identified another class of CNVs that are
frequently inherited and associated with variable expressivity. We previously identified a 520-kbp deletion on
chromosome 16p12.1 that was associated with multiple neurodevelopmental outcomes, including intellectual
disability/developmental delay (ID/DD), schizophrenia, autism, and epilepsy. This variant is inherited in >95%
of cases from carrier parents manifesting neuropsychiatric features. We also found that affected children with
the deletion were more likely to carry another large CNV or rare deleterious mutation elsewhere in the genome
compared to carrier parents. Thus, while the 16p12.1 deletion confers significant risk for a range of disorders,
the ultimate phenotypic trajectory is determined by variants in the genetic background. Functional assessment
of the deletion would therefore provide a novel cellular paradigm for how the same variant confers
susceptibility to distinct neurodevelopmental disorders. Here, we propose to study induced pluripotent stem
cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMC) from three families with the
16p12.1 deletion, each including two or more affected children who manifest severe ID/DD or autism, carrier
parents with neuropsychiatric features, and unaffected non-carrier parents. We will generate neural progenitor
cells (NPCs) and differentiated cortical neurons from 12 individuals from three families, including affected
children with either severe ID or autism, carrier parents with neuropsychiatric features, and non-carrier parents,
and assess the impact of the deletion during different timepoints of neuronal development, including in neural
progenitor cells (NPCs) and differentiated cortical neurons. In Aim 1, we will assess cellular properties of
iPSC-derived NPCs, including cell proliferation, cell cycle, and apoptosis, and perform RNA sequencing of
NPCs to identify gene expression changes and altered biological pathways. To assess the effect of the
deletion independent of the genetic background, we will also generate a CRISPR/Cas-9 mediated deletion in
an isogenic background and compare with controls. In Aim 2, we will differentiate the NPCs to cortical
neurons, and perform a series of assays to measure changes in neuronal properties such as soma size,
dendritic length and complexity, and synaptic development, as well as changes in action potential and firing
properties. These results will be integrated with transcriptomic and available experimental data from Drosophila
and X. laevis models for homologs of individual genes within the 16p12.1 region, in order to identify the
mechanistic signatures associated with the 16p12.1 deletion. Overall, our proposal aims to establish human
iPSC models for the 16p12.1 deletion as a cellular paradigm to understand risk fo...

## Key facts

- **NIH application ID:** 10235289
- **Project number:** 1R21NS122398-01
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Santhosh Girirajan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $428,267
- **Award type:** 1
- **Project period:** 2021-06-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235289

## Citation

> US National Institutes of Health, RePORTER application 10235289, Cellular Basis for Genetic Susceptibility to Neurodevelopmental Disorders (1R21NS122398-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235289. Licensed CC0.

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