Uncovering Patterns in Genetic Uncertainty: Advances in Inborn Errors of Immunity

Behind every medical mystery lies a patient seeking clarity and tailored care. In cases of suspected inborn errors of immunity (IEIs), genetic testing plays a crucial role in guiding diagnosis and treatment. However, these tests often reveal gene variants of uncertain significance (VUS)—DNA changes detected but not yet classified as harmful or benign—adding complexity to clinical decision-making.

Recent research from Yale School of Medicine, published in Clinical Immunology, offers a new perspective on these ambiguous results. The study suggests that VUS can hold meaningful clinical clues and should be examined more closely. Dr. Junghee Jenny Shin, senior author and director of Yale Medicine's Primary Immunodeficiency Program, notes that approximately 80% of patients undergoing genetic testing for IEIs receive a VUS, which can be frustrating but potentially valuable.

People with IEIs are born with immune system impairments, leading to recurrent infections, autoimmune issues, autoinflammatory conditions, and increased cancer risk. Traditionally, clinicians have avoided making treatment decisions based solely on VUS results, but emerging evidence indicates that patterns within these variants may reflect specific clinical phenotypes.

To explore this, researchers compiled patient data into a comprehensive database, focusing on individuals with suspected IEIs. They identified over 200 VUS and grouped them according to gene function. The analysis revealed that certain clusters of VUS correlated strongly with particular clinical features. Notably, variants associated with the adaptive immune system—namely B cells, which produce antibodies, and T cells, which coordinate immune responses—showed distinct patterns.

For example, VUS in B-cell-related genes were linked to recurrent respiratory infections and the need for immunoglobulin replacement therapy. Conversely, VUS affecting T-cell pathways were associated with autoimmune and overactive immune responses. These findings suggest that analyzing VUS collectively can uncover patterns that might otherwise be overlooked, moving beyond the traditional functional experiments.

While functional studies remain the gold standard for assessing genetic variants, they are resource-intensive and not always feasible in everyday clinical settings. This innovative approach of pattern recognition in VUS does not replace detailed laboratory testing but provides a new way to interpret genetic data, potentially accelerating diagnosis and personalized treatment.

This study exemplifies the power of interdisciplinary collaboration, involving trainees and faculty across Yale's departments. By integrating clinical insights with genetic data, the team has taken a significant step toward better understanding the genetic underpinnings of IEIs and improving patient care.

Source: MedicalXpress