Researchers from the Icahn School of Medicine used a novel genetic sequencing technology to identify the genetic cause of--and a treatment for--a previously unknown severe auto inflam-matory syndrome affecting an 18-year-old girl since infancy.
The technology, tailored to the patient's own genetic code at a single cell level, helped the re-searchers characterize an unknown mutation in a gene called JAK1 that caused the patient's immune system to be permanently turned on, resulting in rashes over much of her skin, growth abnormalities, kidney failure, allergic hypersensitivities, and an unusual inflammatory condi-tion throughout the digestive tract.
The study, led by Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, at the Icahn School of Medicine at Mount Sinai, faculty member of The Mindich Child Health and Development Institute and the Precision Immunology Institute at Mount Sinai, and Director of the Center for Inborn Errors of Immunity, was published in the August 3 issue of the journal Immunity. The discovery points toward new ways to study how genetic diseases manifest and presents a model of personalized diagnosis and treatment for patients with genetic diseases.
Autoinflammatory diseases are caused by abnormal activation of the immune system, leading to recurrent episodes of inflammation that may result in damaged or failed organs. The researchers determined that not all of the patient's cells carried this mutation and had different genetic makeups or genotypes, what the researcher describe as a mosaic.
"Most genes use both their maternal and paternal copies, called alleles," said Dr. Bogunovic. "Our findings show the JAK1 mutation in this patient used only one copy per cell, known as monoallelic expression. This challenges the textbook principles of genetics and may help ex-plain irregularities that are frequently encountered across genetic diseases."
In the paper, the researchers describe the use of next-generation genomic, molecular, and multi-parametric immunological tools to probe the effects of the patient's JAK1 mutation. By map-ping the genotype of JAK1 across the patient's body, researchers were able to pinpoint precisely when the mutation arose in early development in the embryo. It later gave way to a host of symptoms from early childhood to early adulthood. The hunt began for a specific therapy that would curb the excessive activity of her mutant JAK1 and potentially cure her inflammatory symptoms.
"We identified one drug, tofacitinib, a JAK inhibitor, that curbed the excessive activity of her hyperactive inflammation. When administered the therapy, she rapidly improved within weeks. Her skin lesions cleared, her daily gastrointestinal symptoms resolved, and the clinical signs of inflammation went away, putting the patient in remission for two years until her unfortunate demise from coronavirus-related illness," said Dr. Bogunovic. "This research helps better un-derstand the basic function of JAK1, which has broad implications for diseases of the immune system and how to treat them. In addition, the genetic discoveries uncovered in this case open up new research avenues into the complexities of how genetic diseases manifest and present a model of the future of personalized medicine. By coupling advanced clinical care with next-generation sequencing and detailed laboratory studies, we successfully diagnosed and treated a life-threatening disease."
The research was accomplished with collaboration from the Vagelos College of Physicians and Surgeons at Columbia University Irving Medical Center, The Rockefeller University and New York University Grossman School of Medicine in New York City and the Universite de Nantes and Centre Hospitalier Universitaire de Nantes in Nantes, France.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encom-passing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality care--from prevention to treatment of the most se-rious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in the country. Mount Sinai Health Sys-tem hospitals are consistently ranked regionally by specialty by U.S. News & World Report.
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