# HIGHLY PARALLEL ANALYSIS OF 5' AND 3' UTR VARIANTS IN NEURODEVELOPMENTAL DISORDERS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $775,004

## Abstract

ABSTRACT
Substantial investments are being made to sequence the genomes of families with autism and other
neurodevelopmental disorders (NDD). However, identifying disease mutations outside the ~1% of protein
coding sequences is challenging because 1) the ‘search space’ is much larger, and thus many more mutations
occur by chance, and 2) there is no simple code to identify deleterious mutations in non-coding sequences,
and thus loss of function mutations must be defined experimentally. In addition, the consequences of mutations
in non-coding (i.e. regulatory) sequences are often highly dependent on the specific cell type. Thus, functional
assays must be conducted in vivo, in the appropriate CNS cell types.
To address the search space challenge, we have focused specifically on the untranslated regions (UTRs)
of mRNAs. UTRs are important, conserved regulatory sequences that profoundly impact protein levels by
altering translation rates or transcript stability for specific genes. To address the lack of a code for interpreting
UTR mutations, we have developed a unique combination of expertise to conduct massively parallel
functional analysis of UTR variants from NDD patients, in relevant cell types in the brain. Combining
two innovative but established components: massively parallel reporter assays, and cell type specific
translational profiling, we aim to establish a pipeline to 1) Identify UTR mutations that result in altered protein
levels, 2) conduct genetic burden and association testing on these variants, and 3) train machine learning
models that can predict the effects of future mutations in developing neurons of the brain. This project will
leverage the existing large investment in NDD genome sequencing by defining individual non-coding, disease-
causing mutations in a class of sequences that has, so far, not been the focus of disease studies.

## Key facts

- **NIH application ID:** 10981836
- **Project number:** 2R01MH116999-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JOSEPH D DOUGHERTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $775,004
- **Award type:** 2
- **Project period:** 2018-06-19 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981836

## Citation

> US National Institutes of Health, RePORTER application 10981836, HIGHLY PARALLEL ANALYSIS OF 5' AND 3' UTR VARIANTS IN NEURODEVELOPMENTAL DISORDERS (2R01MH116999-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981836. Licensed CC0.

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