# Discovering Splicing Defects in Human Genes

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $597,181

## 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 4,972 disease
alleles that revealed 10% of exonic mutations affect splicing. The pilot study also revealed that
splicing mutations are not uniformly distributed across disease genes. Preliminary results
identify 64 diseases significantly more likely to be caused by a splicing mutation. This proposal
will utilize a reporter system to test the effect of substitutions and in/dels on splicing and to
annotate splicing element in medically relevant genes. The data set created by this approach
will be used to train an online splicing mutation prediction tool. This project will also screen all
variants that fall within 75nucleotides of a splice site in the set of 130 “actionable genes”. The
study will utilize a variety of cell lines reflecting distinct tissues of origin and determine which
stage of spliceosome assembly is disrupted to provide better characterization of these variants.
Finally, Geisinger HealthCare System GHS in partnership with Regeneron (RGN)
Pharmaceuticals has created a unique dataset of paired genotypic and phenotypic data. The
GHS MyCode project has enrolled over 160,000 patients and completed whole exome
sequencing (WES) on over 60,000 of those patient samples. This set will be used to identify
(and verify) carriers of variants predict to alter splicing. A deep re-phenotyping of patients to
asses the contribution of splicing defects to EHR QTLs, age of onset, severity, penetrance and
differential engagement across multiple organ systems).

## Key facts

- **NIH application ID:** 10222718
- **Project number:** 5R01GM127472-04
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** William G Fairbrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $597,181
- **Award type:** 5
- **Project period:** 2018-08-23 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222718

## Citation

> US National Institutes of Health, RePORTER application 10222718, Discovering Splicing Defects in Human Genes (5R01GM127472-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10222718. Licensed CC0.

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