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Stanford University School of Medicine

New genome sequencing method helps diagnose a rare genetic condition

When the race to sequence the human genome was reaching a fever pitch in the early 2000s, when I was in high school, I couldn't help but wonder, "What comes next?" Once we had full access to our genetic blueprint, what more was there to do?

As it turned out, the understanding of human genetics is much more complicated than I'd imagined as a teen. And understanding how human health hinges upon the strings of molecular letters within our DNA isn't always easy, either.

Researchers at Stanford, in collaboration with the biotechnology company Pacific Biosciences, are working to push past some of the limitations of current sequencing technology. Their goal is to make full-genome sequencing accessible for clinical use. The team has used a new sequencing technology -- called long-read sequencing -- in a patient for the first time. I described their work in a press release:

Current sequencing technologies cut DNA into 'words' that are about 100 base-pairs, or letters, long, according to the study's senior author, Euan Ashley, DPhil, FRCP, professor of cardiovascular medicine, of genetics and of biomedical data science at Stanford. Long-read sequencing, by comparison, cuts DNA into words that are thousands of letters long.

'This allows us to illuminate dark corners of the genome like never before,' Ashley said. 'Technology is such a powerful force in medicine,' he added. 'It's mind-blowing that we are able to routinely sequence patients' genomes when just a few years ago this was unthinkable.'

In this study, which appears in Genetics in Medicine, the team used long-read sequencing to examine a part of Ricky Ramon's genes that hadn't been successfully sequenced with current technology. Ramon, who is 26, has had benign tumors throughout his body since he was about 7 years old, but doctors couldn't pinpoint a diagnosis. Especially problematic were the tumors in Ramon's heart, which required open-heart surgery to remove.

The team thought Ramon's symptoms were indicative of Carney complex, an extremely rare genetic condition, but the sequencing method they used initially did not identify any changes to the gene responsible.

Carney complex arises from mutations in the PRKAR1A gene, and is characterized by increased risk for several tumor types, particularly in the heart and hormone-producing glands, such as ovaries, testes, adrenal glands, pituitary gland and thyroid. According to the National Institutes of Health, fewer than 750 individuals with this condition have been identified.

The most common symptom is benign heart tumors, or myxomas. Open heart surgery is required to remove cardiac myxomas; by the time Ramon was 18 years old, he'd had three such surgeries.

The long-read sequencing gave Ramon's team of doctors at Stanford a confirmed diagnosis of Carney complex, which allows them to make better-informed recommendations about his treatment.

Though having confirmation of a permanent genetic condition can be disheartening at times, Ramon told me: "I'm in good hands... I'm glad to be here."

Previously: Clinical guidance on genetic testing: A Q&A, New tool to ID disease-causing genetic changes developed at Stanford and Mystery solved: Researchers use genetic tools to diagnose young girl's rare heart condition
Photo by MIKI Yoshihito

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