# Cellular Phenotypes of Genetic Variants in Mucopolysaccharidosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $436,544

## Abstract

ABSTRACT
There is presently an urgent need to develop methodical approaches to evaluate the function of genomic vari-
ants. Clinical genomic testing is growing rapidly, and with it a larger-than-ever number of genetic variants that
cannot be defined as either disease-causing or benign. The problem affects clinicians and their patients, who
struggle to understand and interpret molecular diagnostic reports, the implications of the results, and how to
manage their patients in the absence of definitive information. Systems that involve single cells to generate
high-content, high-resolution functional data are of paramount importance to solving the problem posed by var-
iants of uncertain significance. Here, we propose to utilize a novel cell-based platform that uses machine learn-
ing to determine the combination of morphological phenotypes that define pathogenicity. We will apply the
technology to the comprehensive functional assessment of variants in IDS, the gene responsible for Hunter
syndrome. The core hypothesis outlined in this proposal is that experimental data measuring the direct func-
tional effects of variants will inform accurate disease risk prediction. In addition, we hypothesize that an in vitro,
cell-based assay based on morphological features will more accurately detect disease compared to existing
biochemical testing using artificial substrates. We will perform a functional assay in a variant library using the
RaftSeq pipeline in the Buchser laboratory, where a cellular phenotype will be established and then tested us-
ing a second set of variants combined with rescue experiments. The results will inform variant classification in
IDS molecular testing and improve diagnosis of individuals including those identified by low iduronate-2-sulfa-
tase activity on newborn screening.

## Key facts

- **NIH application ID:** 10813739
- **Project number:** 5R01NS132057-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** William J Buchser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,544
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813739

## Citation

> US National Institutes of Health, RePORTER application 10813739, Cellular Phenotypes of Genetic Variants in Mucopolysaccharidosis (5R01NS132057-02). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/10813739. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*