Finding the needle in the haystack: a tool for rare inherited diseases

Research

Finding the needle in the haystack: a tool for rare inherited diseases

By
Mayo Clinic Staff

October 23, 2019

Individualized medicine has had notable success in identifying DNA mutations that cause cancer. But rare inherited diseases pose an even bigger challenge. Like a needle in a haystack, the cause of a rare inherited disease is often deeply buried, in the DNA that comprises genes or controls their expression. Now however, Mayo Clinic's Center for Individualized Medicine has developed a tool to pinpoint RNA aberrations that underlie rare inherited diseases, paving the way for increased diagnosis.

"Individuals with these diseases have usually been through a years-long odyssey of traditional medical testing and profiling without success," says Gavin Oliver, a Mayo Clinic informatics specialist. "Identifying a specific cause offers the patient and family the potential for treatment options, reproductive counselling and — not least — the peace of mind of knowing a cause with certainty."

Current genomic testing for rare inherited diseases compares a patient's DNA to the DNA of family members and to databases of healthy individuals' DNA. Those comparisons might uncover a difference in the patient's DNA that can be tied to the physical characteristics of his or her disease.

"But DNA sequencing yields a diagnosis in only about 25% of rare disease patients," Oliver says. "The addition of RNA-based testing has been shown in some studies to improve that rate to as much as 60%. DNA tells us a lot, but the ability to actively profile what the DNA produces — that is, the RNA transcripts — offers us a whole new perspective."

Filtering RNA's noise

Mayo’s new tool focuses on an RNA aberration known as fusion transcription. Although fusion transcripts have been linked to blood and solid tissue cancers, they haven't been widely investigated in rare genetic diseases. Identifying these RNA errors, which result in individual genes being abnormally joined, is daunting.

"RNA is very noisy data," Oliver says. "When we analyze it, we see a lot of artifacts from random occurrences. Much of this noise is due to imperfections of the computer programs, errors caused by laboratory protocols or perhaps biological events that aren't relevant to the patient's disorder."

Mayo researchers succeeded in filtering that noise, to isolate verifiable fusion transcripts. In a study of the new approach, 47 people with undiagnosed, suspected inherited disease had RNA sequencing performed. The results were analyzed using an existing fusion transcription algorithm originally designed for cancer data, with all the filters aimed at cancer data turned off.

The initial result was large haystacks — roughly 31,000 candidate fusion events per study participant. But after creating their own filters aimed at rare genetic diseases, the researchers reduced that number to about 12 candidates per patient.

Eleven candidates with the highest potential relevance to the patients' conditions were then investigated in the laboratory. Eight of the 11, or 75%, were confirmed as genuine RNA fusion transcripts. Two were judged clinically diagnostic of the patients' conditions.

"Initially, we had to consider everything, including the noise, as a fusion transcript candidate. But we were able to reduce the noise and obtain a manageable number of events to investigate in the lab," Oliver says. "The two cases we solved using fusion transcript analysis had gone unsolved for years, despite wide-ranging clinical and research testing. More follow-up is required to confirm the role of the remaining nine events."

"Fusion transcript detection definitely won't solve every case of rare inherited disease, but it can contribute. Every patient diagnosed is a huge victory. The true goal is 100% diagnosis."
Gavin Oliver

The study represents the first systematic application of fusion transcript detection in people with undiagnosed, rare inherited diseases. The patients in the study had a wide range of rare conditions, including neurological, immune, muscular, digestive, connective tissue and skeletal disorders. The new method of fusion transcription analysis will be used routinely at Mayo Clinic for every patient with an undiagnosed rare disease whose RNA is sequenced.

"Fusion transcript detection definitely won't solve every case of rare inherited disease, but it can contribute," Oliver says. "Every patient diagnosed is a huge victory. The true goal is 100% diagnosis."