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Sequencing Uncovers Mutation, Treatment for Rare Genetic Autoimmune Disorder

NEW YORK – Through a personalized sequencing approach, researchers not only uncovered the mutation behind a patient's unknown autoimmune disorder disease, but also a therapy to treat it. 

Researchers from the Icahn School of Medicine studied the patient, an 18-year-old girl who presented with a range of symptoms hinting at widespread immune dysregulation, as part of an undiagnosed disease program. By sequencing her and her parents, the researchers homed in on a variant in the JAK1 gene, which encodes a kinase involved in key signaling processes. 

As they reported Monday in the journal Immunity, the researchers found that this variant increases JAK1 activity and downstream signaling activity. But they also found that a JAK inhibitor alleviates that activity and resolved some of the patient's symptoms.

"By coupling advanced clinical care with next-generation sequencing and detailed laboratory studies, we successfully diagnosed and treated a life-threatening disease," senior author Dusan Bogunovic, an associate professor of microbiology and pediatrics at Mount Sinai, said in a statement.

The findings, he added, "open up new research avenues into the complexities of how genetic diseases manifest and present a model of the future of personalized medicine."

The patient was referred to the Mount Sinai undiagnosed disease program with autoinflammatory symptoms including a widespread rash at birth; recurrent diarrhea and vomiting around one year of age; edema and protein in her urine around the age of three; and kidney complications that led to a transplant by age 11. She also developed asthma, food and environmental allergies, and had poor weight gain.

Whole-exome sequencing of her and her healthy parents did not at first reveal any likely recessive variants contributing to disease. But when the researchers searched for lower-read-frequency de novo mosaic mutations, they uncovered a JAK1 variant present in 27 percent of reads that leads to a serine-to-isoleucine substitution at a highly conserved site.

Through a series of experiments in cell lines, the researchers found that this alteration leads to the hyperphosphorylation of JAK1 as well as of proteins that interact with JAK1, indicating it enhances downstream signaling. However, they noted that this gain-of-function change did not necessarily lead to the activation of all downstream pathways, as some appeared to not be affected.

The researchers additionally noted the patient was mosaic for this alteration and traced its emergence to early embryonic development, sometime during the first dozen cell divisions. At the same time, they found through single-cell analyses that there appeared to be monoallelic expression of JAK1, which they said could have implications for other monogenic diseases. 

"This challenges the textbook principles of genetics and may help explain irregularities that are frequently encountered across genetic diseases," Bogunovic said.

He and his colleagues then examined whether JAK inhibitors might treat her condition. In cells and blood derived from the patient, they examined the effects of two pan-JAK inhibitors approved by the US Food and Drug Administration. One — tofacitinib — appeared to inhibit the effect of the variant more strongly, which led to the patient being treated with it at a low dose. Within two months, her inflammatory markers normalized, and her dermatological and gastrointestinal symptoms improved. She remained stable for two years following treatment until dying of acute respiratory failure due to COVID-19.

Still, the researchers reported that their findings underscore the value of studying patients from undiagnosed disease programs and provide a workflow to search for optimal personalized therapies for such patients.

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