# Cortical organoid models to study autism-associated 16p.11.2.CNV

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $706,333

## Abstract

SUMMARY
The 16p11.2 Copy Number Variant (CNV) containing 29 genes represents one of the strongest risk factors for
neurodevelopmental disorders. It is the most common among all rare CNVs implicated in Autism Spectrum
Disorder (ASD). Both, deletions (DEL) and duplications (DUP) of this locus are strongly associated with ASD,
whereas DEL are also associated with intellectual disability, and DUP are also associated with schizophrenia.
The 16p11.2 CNV dosage has “mirror” effect on the brain volume and body mass index (BMI) in human carriers
diagnosed with ASD. Macrocephaly and high BMI are observed in the DEL carriers, and microcephaly and low
BMI are observed in the duplication carriers. Surprisingly, 16p11.2 DEL and DUP mouse models have brain and
body size phenotypes opposite to human carriers. Despite the importance of this CNV, the detailed molecular
mechanisms that are disrupted during early brain development remain unknown. We recently generated induced
pluripotent stem cells (iPSCs) and cerebral organoids from fibroblasts of 16p11.2 DEL and DUP patients with
extreme head size phenotypes. Cerebral organoids recapitulated patients’ brain size phenotypes. Excess neuron
number and depletion of neuroprogenitors was observed in DEL, with a “mirror” phenotypes in DUP. In addition,
neuron migration and synaptic defects were identified, implicating Rho/Wnt signaling. The central hypothesis
of this proposal is that that 16p11.2 CNV dosage (DEL or DUP) impacts brain development by altering
the ratio of different neuronal (sub)types and by perturbing their electrophysiological properties. To test
this hypothesis, we will: (1) Investigate how 16p11.2 CNV impacts cell type populations and chromatin
accessibility at the single cell resolution; (2) Investigate how 16p11.2 CNV affects synaptic transmission and
oscillatory network activity in organoids using whole-cell patch-clamp and multielectrode array (MEA) recordings;
Investigate involvement of Rho/Wnt and other signaling pathways by rescuing molecular and cellular phenotypes
of DEL and DUP organoids. Our study has a potential to uncover new mechanisms behind 16p11.2 CNV in
autism.

## Key facts

- **NIH application ID:** 10537569
- **Project number:** 1R56MH128365-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** LILIA M IAKOUCHEVA
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $706,333
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537569

## Citation

> US National Institutes of Health, RePORTER application 10537569, Cortical organoid models to study autism-associated 16p.11.2.CNV (1R56MH128365-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10537569. Licensed CC0.

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