# Discovering Splicing Defects in Human Genes

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $701,521

## Abstract

Project Summary/Abstract
It is currently feasible for small research groups to sequence individual genomes and for larger groups to
sequence tens of thousands of individuals. Unfortunately, our ability to identify variants that impact phenotype
has not kept pace with our sequencing capacity. This is particularly true of non-coding variants. This proposal
presents 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. 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.

## Key facts

- **NIH application ID:** 10902018
- **Project number:** 5R01GM127472-06
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** William G Fairbrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $701,521
- **Award type:** 5
- **Project period:** 2018-08-23 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902018

## Citation

> US National Institutes of Health, RePORTER application 10902018, Discovering Splicing Defects in Human Genes (5R01GM127472-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10902018. Licensed CC0.

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