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Immune system disorders encompass infrequent hereditary conditions that compromise the immune response, making individuals susceptible to severe infections and additional complications like autoimmunity, inflammation, and malignancies. Although a formidable diagnostic resource, genetic examination— which detects alterations, or mutations, in an individual’s genetic composition— has brought to light approximately 550 such disorders but still leaves 70% of individuals with suspected immune deficiencies undiagnosed.
Megan A. Cooper, MD, PhD, the Anthony R. French, MD, PhD, Professor of Pediatrics at Washington University School of Medicine in St. Louis, has been awarded a five-year $12.4 million grant from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH) to investigate genetic mechanisms overlooked by standard genetic testing that may contribute to immune disorders in both children and adults. This inquiry could uncover new genetic origins of immune disorders and provide insights for patients awaiting a diagnosis.
“The diagnosis rate for rare immune disorders has not improved over the past decade,” stated Cooper, a globally recognized physician-scientist focusing on diagnosing and treating rare genetic illnesses that impact the immune system, particularly in children. “Effective interventions depend on comprehending the precise issues within a patient’s immune response. A diagnosis facilitates access to targeted therapies, efficient disease management, and preventive measures.”
For those with potential immune deficiencies, symptoms can be vague and include extended fevers following common infections, such as respiratory ailments; frequent atypical infections; autoimmune conditions; susceptibility to cancers; and severe allergies, among others. No two patients present the same symptoms, Cooper elaborated, which complicates the diagnosis of immune disorders.
“I encounter numerous patients who are frequently unwell,” Cooper remarked, who collaborates with specialists globally to resolve complex diagnostic challenges faced by children. “When we are uncertain of the cause behind their symptoms, we are left to administer rather broad, non-specific therapies that can sometimes prove ineffective. This research aims to furnish more families with life-saving molecular diagnoses that can inform treatment.”
Discovering new genetic origins
Genetic testing identifies variations in an individual’s DNA and is adept at recognizing errors that exist from the outset of development and affect all cells in the organism. Mutations that develop over time within cells, which are rare in the organism or impact only specific tissue types, are much more difficult to detect using standard genetic sequencing.
To address this challenge, Cooper and two associates at Columbia University Vagelos College of Physicians and Surgeons in New York City — Dusan Bogunovic, PhD, an immunologist and professor of pediatrics, and a co-principal investigator on the grant, and Joshua Milner, MD, an immunologist and professor of pediatrics — will employ a method known as deep sequencing, which permits them to scrutinize genes in patients with a level of precision and accuracy unattainable by standard sequencing, aiding in the identification of changes that influence even a minuscule number of cells.
Under Bogunovic’s guidance, they will also examine a distinctive genetic process that can lead to some family members being affected by illness, while others remain unaffected, despite all members inheriting one defective and one functional copy of a gene. Whether a family member stays healthy or experiences disease is contingent upon which gene variant remains active. The research aims to pinpoint genes in the immune system that exhibit this pattern and to enhance the understanding of the regulatory factors involved.
The approximately 550 recognized immune disorders arising from various genetic changes result in symptoms that are markedly diverse and individualized. Another area of focus, spearheaded by Milner, aims to investigate how combinations of common genetic alterations— rather than isolated gene mutations— influence an individual’s likelihood of illness and its severity. They will analyze the effects of these common alterations in patient cells, correlating patient symptoms with the combination of genetic changes present.
The newly awarded grant is based on initial data that applied deep sequencing to explore genetic differences linked to immune disorders. That research was funded by the NIH, St. Louis Children’s Hospital Foundation, and the Children’s Discovery Institute, a partnership between St. Louis Children’s Hospital, its foundation, and WashU Medicine, aimed at finding innovative, more precise, and personalized solutions for a variety of childhood diseases.
Other WashU Medicine researchers involved include Obi L. Griffith, PhD, a professor, and Malachi Griffith, PhD, an associate professor, both in the John T. Milliken Department of Medicine.
About Washington University School of Medicine
WashU Medicine is a prominent authority in academic medicine, encompassing biomedical research, patient care, and educational initiatives with 2,900 faculty members. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has increased by 83% since 2016. In conjunction with institutional investment, WashU Medicine allocates over $1 billion annually to basic and clinical research innovation and training. Its faculty practice consistently ranks among the top five in the nation, with more than 1,900 faculty physicians serving at 130 sites. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children’s hospitals — the academic facilities of BJC HealthCare — and treat patients at BJC’s community hospitals across the region. WashU Medicine has a distinguished history in MD/PhD education, having recently dedicated $100 million to scholarships and curriculum enhancement for its medical students, and is home to high-quality training programs across all medical subspecialties, as well as physical therapy, occupational therapy, and audiology and communication sciences.
Originally published on the WashU Medicine website
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