Greenwood Genetic Center’s functional platform for newborn screening variants leads to treatment project

Greenwood, SC (April 7, 2025) – The National MPS Society has awarded a $100,000 grant to Rich Steet, PhD, Director of Research at the Greenwood Genetic Center (GGC). Steet will lead the two-year project that expands upon prior work to better understand the significance of rare genetic variants in the IDUA gene that causes Mucopolysaccharidosis Type I (MPS I). This new funding will also support research into personalized or variant-specific therapies for patients with MPS I.

MPS I, also known as Hurler, Scheie, or Hurler-Scheie syndrome, is a rare lysosomal storage disorder caused by the inability of the body’s cells to produce enough of an enzyme called alpha-iduronidase that breaks down glycosaminoglycans. The toxic buildup of these substances leads to symptoms including coarse facial features, hearing loss, skeletal deformities, cardiac issues, and developmental delays.

“In recent years, MPS I has been added to the newborn screening panels in most US states, which is vital to making an early diagnosis and initiating early treatments,” said Steet. “However, this increased screening is leading to the identification of more variants of uncertain significance, raising questions about which variants are actually disease-causing and uncertainty of how or if to treat these infants.”

With prior support from the National MPS Society, Steet’s lab and their colleagues in GGC’s Biochemical Genetics Laboratory have developed a platform to functionally assess these variants to determine their impact and offer a clear diagnosis to inform medical management and treatment decisions. The lead researcher on this project is GGC Senior Staff Scientist, Dr. Seok-Ho Yu.

“The new platform allows us to determine the relative specific activity of these variant enzymes, which compares the amount of enzyme activity produced by the gene variants to the activity we should see with a typical gene,” said Laura Pollard, PhD, Director of GGC’s Biochemical Genetics Laboratory. “To date, we have characterized thirty-five variants in the IDUA gene, allowing us to predict whether each of these variants is expected to cause symptoms of MPS I.”

These findings were published in npj Genomic Medicine in late 2024, and the development of this research platform has led to additional work supporting clinical providers around the country to clarify what impact these variants have on symptoms.

“As newborn screening expands, we are uncovering more variants of unknown significance which impacts treatment decisions and also leads to parental anxiety,” said Francyne Kubaski, PhD, Staff Scientist in GGC’s Biochemical Genetics Laboratory. “As we improve the ability to clarify these variants through protocols such as our IDUA platform and analyses by mass spectrometry of lysosomal storage, we will have more tools available to support newborn screening follow-up for other genes and conditions as well.”

The project is now expanding to investigate potential personalized treatments for some of these MPS I variants.

“This new National MPS Society grant will take this project in a new direction by looking at specific gain-of-glycosylation variants that interfere with enzyme activity because of the addition of extra sugar chains to the MPS I enzyme,” said Heather Flanagan-Steet, PhD, a lead researcher on the project. “If we can prevent those new sugar chains from being added, this may offer a personalized therapy specifically for patients with those variants.”  

The team’s advancements have also prompted a complementary project with Gene Spotlight, a leading medical research non-profit organization, on GGC’s first high-throughput drug screen for patients with a specific variant in the gene that causes MPS I. GGC researchers are screening approximately 1,800 compounds, most of which already have FDA approval for other purposes, to determine if they increase the activity of the alpha-iduronidase enzyme in cells with a specific MPS I variant.

“We are excited about the expansion of this project and are grateful for our longstanding collaboration with the National MPS Society,” said Mike Lyons, MD, Chief Genomics Officer and Curry Chair in Translational Genomics and Therapeutics at GGC. “As GGC fulfills our strategic precision medicine initiative, this work will be instrumental in not only providing clarity and answers for more rare disease patients but also allowing us to act on those discoveries with personalized treatments to improve each patient’s quality of life.”

About Greenwood Genetic Center

The Greenwood Genetic Center (GGC), founded in 1974, is a nonprofit organization advancing the field of medical genetics and caring for families impacted by genetic disease and birth defects.  At its home campus in Greenwood, South Carolina, a talented team of physicians and scientists provides clinical genetic services, diagnostic laboratory testing, educational programs and resources, and research in the field of medical genetics.  GGC’s faculty and staff are committed to the goal of developing preventive and curative therapies for the individuals and families they serve.  With partners at the Medical University of South Carolina (MUSC), GGC extends its reach as a resource to all residents of South Carolina with satellite offices in Charleston, Columbia, Florence, and Greenville. For more information about GGC, please visit www.ggc.org or www.musc.edu.

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