Incomplete Penetrance in Autoinflammatory Diseases

CHICAGO—Inherited autoinflammatory and autoimmune diseases often display striking variability, even among family members with the same genetic mutation. This phenomenon, known as incomplete penetrance, has long intrigued researchers. At ACR Convergence 2025, in the session Old Dog, New Tricks: Regulation of Autoinflammation and Autoimmunity Informed by Inborn Errors of Immunity, Dusan Bogunovic, PhD, explored an emerging explanation: monoallelic expression (MAE). Drawing on his groundbreaking research as professor of pediatric immunology and director of the Center for Genetic Errors of Immunity at Columbia University, New York, Dr. Bogunovic described how MAE may shape the variable expression of autoimmune and autoinflammatory phenotypes.

Genetic Underpinnings of Disease

Dusan Bogunovic, PhD, Columbia University Medical Center

Dr. Bogunovic began by defining inborn errors of immunity (IEI) as genetic disorders that predispose to susceptibility to infections, autoinflammation, autoimmunity, allergy and malignancy. “Canonically, we used to think of them [inborn errors of immunity] as primary immunodeficiencies,” he said, but they are also capable of immune dysregulation. Therefore, patients with IEI may present to rheumatology clinics with various autoimmune and autoinflammatory phenotypes.

He recalled the most famous case of immunodeficiency, known to many as the “boy in the bubble.” The patient had severe combined immunodeficiency (SCID) and, effectively, no functioning immune system. The discovery of SCID was made in the 1960s, and since then, more than 600 unique, monogenic IEIs have been identified, accelerated by the advent of next-generation sequencing. Although these IEIs are thought of as rare, the collective group of monogenic diseases affects one in 800–1,000 people.

Dr. Bogunovic described forward genetics, the conventional pathway by which a new IEI is identified: a patient presents with a unique phenotype suspected of being monogenic, undergoes genetic sequencing and if a single causal mutation is identified, a new IEI is found. In the ideal situation, precision medicine facilitates development of a novel therapy directed to this single mutation.

He stated, however, that “medicine is complicated; it’s never linear and as dreamy as you want it to be.” This complexity is in part, due to incomplete penetrance, which means that a patient with a genetic variant does not manifest the disease clinically. Some patients carrying a mutation may have a partial phenotype or partial disease expressivity. Likewise, a sibling could carry the mutation without a single disease manifestation. Dr. Bogunovic highlighted that very few examples exist in the field of IEI that have 100% penetrance, such that all carriers of the mutation manifest the disease.