# Beyond the Synapse: Convergence of Autism Risk Genes at the Cilium

> **NIH NIH F99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $43,027

## Abstract

PROJECT SUMMARY / ABSTRACT
Autism spectrum disorder (ASD) is a relatively commonneurodevelopmental disorder (NDD), for which hundreds
of large-effect risk genes have been identified. However, the molecular mechanisms underlying ASD remain
unknown. ASD is commonly comorbid with disorders caused by cilia defects, but the possibility that cilia defects
underlie ASD pathogenesis has not been systematically investigated. My dissertation work addresses this gap
in knowledge by investigating the role of large-effect ASD risk genes in cilia formation using complementary
model systems. To date, I have demonstrated that six high-confidence ASD risk genes localize to the cilium and
are required for their formation, using both in vivo Xenopus models and in vitro human cells and transcriptomics.
Included in these genes is the leading ASD risk gene, SYNGAP1, which has a canonical role in synaptic
plasticity. My results show that it also plays a role earlier in brain development at the cilium, reframing its potential
molecular contributions to ASD risk. The work proposed here will dissect the domains of SYNGAP1 necessary
for its localization and function at the cilium using the high-throughput Xenopus model (Aim 1A). Then these
findings will be translated to rodent models to dissect SYNGAP1 localization and function in a neural context,
both at cellular and organ-level resolution using Syngap1 mutant rats (Aim 1B). To model human
haploinsufficiency, we will complement this work by analyzing cilia phenotypes in SYNGAP1 patient iPSC-
derived neurons (Aim 1C). Results from these studies will shift our understanding of the molecular mechanisms
underlying ASD pathogenesis, particularly for the leading ASD risk gene SYNGAP1, with implications for other
‘synaptic’ ASD risk genes. This proposed work and training plan will prepare me for success in the K00 phase
by providing technical training in advanced microscopy, image analysis, tissue processing, bioinformatics, and
iPSC culture, as well as professional skills and intellectual experience in dissecting molecular mechanisms of
NDDs. In Aim 2 (the K00 phase), I will continue to pursue my interests in understanding the molecular
mechanisms of NDDs by investigating the role of lipids in the pathogenesis of NDDs. I will identify a postdoctoral
laboratory that studies NDDs and can support my training in cutting-edge techniques in lipid biology, lipidomics,
and transcriptomics while I develop professional, communication, and inclusive leadership skills. With the tools,
professional skills, and technical skills I develop in the K00 phase, I will be well-positioned to start my
independent research laboratory studying NDDs and create an inclusive environment to lead a diverse team of
trainees and scientists.

## Key facts

- **NIH application ID:** 11001814
- **Project number:** 1F99NS139536-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elina Kostyanovskaya
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,027
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11001814

## Citation

> US National Institutes of Health, RePORTER application 11001814, Beyond the Synapse: Convergence of Autism Risk Genes at the Cilium (1F99NS139536-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11001814. Licensed CC0.

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