# Discovering Splicing Defects in Human Genes

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $227,100

## Abstract

Project Summary / Abstract
The equipment supplement seeks to acquire a PromethION 24 long read sequencer to increase the impact of
the award grant. The parent proposal presented a pilot screen of more than 32K variants from myCode and
ClinVar that suggest 1-2% of exonic mutations affect splicing. The pilot study also revealed that splicing
mutations are not uniformly distributed across disease genes or even within genes. This proposal will continue
this effort on variants from UK biobank, AllofUs, ClinVar and GTEx that localize to actionable genes. Splicing
mutations do not occur uniformly across exons. The proposal seeks to map susceptibility to splicing mutations
and identify hotspot exons (exons unusually susceptible to splicing mutations) in the genome. The long read
sequencer will enable full isoform analysis which will discover complex splicing events that contain multiple
exons. In addition to identifying loss of splicing variants, the little studied problem of gain of splicing variants
(i.e. single base mutations that can activate pseudoexons) will also be explored. Preliminary studies locate
many intronic regions in pre-mRNA that contain all-but-one of the numerous cis-elements necessary for
splicing. In addition to mapping susceptibility to splicing mutations, these efforts will contribute to the basic
science of combinatorial signal recognition with a high-level approach that will define mechanisms of splice site
selection. Finally, we present a principled method of restoring splicing to mutated exons using antisense
oligonucleotides (ASO) that weaken flanking splice sites. Here again long read sequencing will be used to
study splicing in its native state and properly identify complex events.

## Key facts

- **NIH application ID:** 11099242
- **Project number:** 3R01GM127472-06S1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** William G Fairbrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $227,100
- **Award type:** 3
- **Project period:** 2018-08-23 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099242

## Citation

> US National Institutes of Health, RePORTER application 11099242, Discovering Splicing Defects in Human Genes (3R01GM127472-06S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11099242. Licensed CC0.

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