CHOP Using RNA Sequencing to Diagnose Rare Disease

Rare Daily Staff

Researchers at Children’s Hospital of Philadelphia have developed a powerful new technology that could transform how doctors diagnose rare genetic disorders.

The platform, called STRIPE, uses advanced RNA sequencing to spot genetic changes that disrupt how genes function—providing answers for patients whose conditions have remained mysterious even after exhaustive testing.

A study published in the journal Science Advances shows that STRIPE can reveal disease‑causing variants and deliver molecular diagnoses for previously undiagnosed patients. In the study, the tool uncovered new genetic clues in five children who had long gone without explanations for their symptoms.

“RNA is a powerful modality for the diagnosis of rare diseases,” said Yi Xing, associate chief scientific officer for omics, technology, and engineering at CHOP. “By directly observing RNA molecules, we can see how genetic variants alter gene products in ways DNA sequencing alone cannot.”

Traditional genome or exome sequencing reads DNA—the genetic blueprint—but sometimes fails to explain how a mutation actually affects gene function. STRIPE goes one step further by examining RNA, the molecule that carries DNA’s instructions to make proteins. Tracking the full length of RNA molecules can reveal whether genetic variants lead to faulty gene expression or abnormal processing.

Long‑read RNA sequencing, while promising, has been too costly and technically demanding for routine use. CHOP researchers tackled those limits with STRIPE, short for Sequencing Targeted RNAs Identifies Pathogenic Events. They built it on an earlier technology known as TEQUILA‑seq, designed to make long‑read RNA sequencing more affordable. With STRIPE, sequencing a sample costs about $100—low enough for widespread clinical testing.

“STRIPE enables ultra‑deep, full‑length RNA sequencing of disease‑relevant genes at a scale that’s practical for clinical use,” said Lan Lin, assistant professor of pathology and laboratory medicine at CHOP.

To test STRIPE in real‑world conditions, the team focused on patients with congenital disorders of glycosylation (CDG) and primary mitochondrial diseases—two groups of rare disorders extensively studied at CHOP.

A major challenge in diagnosing these diseases is that affected tissues are rarely accessible, said Rebecca Ganetzky, clinical geneticist in CHOP’s Mitochondrial Medicine Program. “STRIPE lets us study RNA from easily collected tissues like skin or blood, yet still captures the disease‑relevant signals,” she said.

In collaboration with CHOP’s CDG Clinic, the researchers analyzed samples from 88 participants. The tool accurately confirmed known mutations, clarified previously uncertain ones, and revealed new causes of disease in several undiagnosed patients.

Since its launch, STRIPE has been used to study more than 500 patient samples across CHOP programs, demonstrating the platform’s scalability and clinical promise.

Beyond helping families find answers, researchers believe STRIPE could pave the way for targeted treatments. By showing how specific genetic variants disrupt RNA molecules, it connects the dots between diagnosis, disease mechanism, and potential therapy.

“STRIPE provides a bridge from genetic diagnosis to disease mechanism to targeted therapies,” Xing said. “We see this as a foundation for RNA‑based precision medicine in rare diseases—linking precision diagnostics directly to precision therapeutics.”

Photo: Yi Xing, associate chief scientific officer for omics, technology, and engineering at CHOP.