# Identifying Pathogenic Non-Coding Mutations in Rare Mendelian Disease

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $236,648

## Abstract

ABSTRACT
Determining new causes for rare and common disease would have major and immediate benefits
for patients and their families by improved genetic testing, genetic counseling, insurance
reimbursement, and ultimately more effective treatment options. Our long term goal is to
disruptively improve and expand genetic testing for rare and common disease. Current diagnostic
tests only consider pathogenic variants in protein-coding genes. However, we now have evidence
that a substantial fraction of rare disease is due to unknown non-coding genetic variants that
influence the regulation of those genes. The goal of this proposal is to identify and quantify
the effect of pathogenic non-coding genetic variants on the function and expression of
genes that cause rare disease. This initial step will enable treatment early in life when it is still
possible to stop the most severe consequences of disease, including death. We will focus on
severe early-onset pediatric disorders, including glycogen storage diseases (GSD I, II, III, IV, and
IX), and the fatty acid oxidation disorders, very long-chain acyl-CoA dehydrogenase deficiency
(VLCAD), and multiple acyl-CoA dehydrogenase deficiency (MADD). To date, genetic tests for
these and other diseases are limited to protein-coding mutations. However, our clinical team has
collected numerous cases that have a single pathogenic coding variant on only one of the two
alleles that must be both affected in these recessive disorders. We also have biochemical and
biomarker evidence that supports the diagnosis. Those cases are an ideal opportunity to identify
additional disease-causing variants. Our hypothesis is that the genetic causes of recessive
disorders include novel genetic variants that can alter either protein sequence (Aim 1), splicing
(Aim 2), or gene expression (Aim 3) of disease genes. We have assembled a team of Pediatric
clinicians who are experts in GSDs, VLCAD, and MADD, as well as researchers who are experts
in genetics, genomics, epigenetic regulation, biomedical engineering, and statistics. This team
has obtained patient samples and received Duke IRB approval to begin immediately. We expect
this study will identify and validate novel genetic variants that influence disease. While we propose
to study a relatively small subset of rare disorders, these strategies will be immediately
generalizable to any patient sample with any recessive disorder that has inconclusive genetic
testing results. That outcome will provide comprehensive genetic testing, better understanding of
disease mechanisms, and ultimately better treatment options.

## Key facts

- **NIH application ID:** 9989881
- **Project number:** 5R21HG010747-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** GREGORY E CRAWFORD
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $236,648
- **Award type:** 5
- **Project period:** 2019-08-07 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989881

## Citation

> US National Institutes of Health, RePORTER application 9989881, Identifying Pathogenic Non-Coding Mutations in Rare Mendelian Disease (5R21HG010747-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9989881. Licensed CC0.

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