# Integrative genomics to map risk genes and pathways in autism and epilepsy

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $761,831

## Abstract

PROJECT SUMMARY
Autism spectrum disorders (ASDs) affect 1% of the general population, and epilepsy (EPI) is observed in at
least one-third of ASD individuals. ASDs with epilepsy (ASD-EPI) are typically more severe and treatment
delay has a negative impact on outcome. The frequent association between epileptic and autistic phenotypes
suggests that they share predisposing genes. Indeed, in recent years it has become clear that genes
implicated in ASD and EPI, as well as other neurodevelopmental disorders, are interconnected in functional
networks. Strikingly, there is a considerable overlap in the networks affected in each disorder, raising questions
on how disruptions of these common networks can give rise to such phenotypical diversity.
Despite ongoing large-scale efforts to identify risk genes for ASD, and to a lesser extent for pediatric EPI, the
diagnostic yield remains low and most causal genes and risk variants are yet to be identified. New cohorts are
also needed to discover additional variants in previously identified candidate genes and elevate them to the
status of ASD-EPI risk genes. Our study differs from previous efforts by focusing on a set of 550 families with a
specific ASD-EPI sub-phenotype that will result in less phenotypic heterogeneity to increase power to find
variants in this specific subtype. For each family we will sequence the complete exome, as well as noncoding
regulatory regions near genes with strong prior evidence for association with ASD and/or EPI. We will perform
burden analysis of rare de novo and inherited gene-disruptive events in ASD-EPI, and correlate with clinical
phenotype variables (early vs late-onset epilepsy, gender, IQ, and MRI abnormalities), and incorporate this into
existing ASD/EPI datasets for gene-set and network analyses, as well as integrating SNVs and CNVs in a
common framework (Aim 1). We will also identify risk variants in noncoding regulatory elements, including cis-
regulatory elements near implicated, high confidence, and/or candidate genes for ASD and EPI (ASD/EPI-
relevant genes), intronic RBFOX binding targets, and miRNA binding targets, using a new statistical framework
followed by burden analyses (Aim 2). Finally, we will functionally characterize 8 high-impact variants, which will
be introduced by CRISPR genome editing into isogenic human induced pluripotent stem cells (iPSCs) and
further differentiated into forebrain neuronal progenitor cells (NPCs) and neurons. Functional assays will include
RNA-Seq, neuronal connectivity and morphology, as well as activity using Multi-Electrode Arrays (Aim 3). The
identification and functional characterization of additional mutations will help prioritize genes and reveal novel
components of the pathways underlying ASD-EPI, and provide mechanistic insight into how they relate to each
other. Our systematic approach also provides the opportunity to classify molecular subtypes of ASD/EPI and to
distinguish how the genetic subnetworks underlying ASD-E...

## Key facts

- **NIH application ID:** 9939703
- **Project number:** 5R01MH110555-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dalila Pinto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $761,831
- **Award type:** 5
- **Project period:** 2016-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939703

## Citation

> US National Institutes of Health, RePORTER application 9939703, Integrative genomics to map risk genes and pathways in autism and epilepsy (5R01MH110555-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9939703. Licensed CC0.

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