D2.382 - Contribution of Clinical and Laboratory Findings to Genetic Testing Decisions and Diagnostic Yield in Patients with Suspected Primary Immunodeficiency

Inborn error of immunity (IEIs) are genetically heterogeneous disorders characterized not only by recurrent infections but also by immune dysregulation, autoimmunity, lymphoproliferation, and malignancy. In current clinical practice, genetic testing decisions are increasingly guided by immune dysregulation features in addition to infection burden. However, the clinical and laboratory parameters that most strongly predict diagnostic genetic yield remain unclear. To evaluate the impact of clinical and immunological features on genetic testing decisions and diagnostic yield in pediatric patients assessed for suspected IEI.

We retrospectively analyzed 123 pediatric patients evaluated for suspected immunodeficiency between January and November 2025. Genetic testing was performed using a 332-gene inborn errors of immunity panel (Sophia DDM Exome Solution, CES). Clinical data were assessed for infection patterns, immune dysregulation manifestations, and family history. Laboratory parameters included immunoglobulin levels, lymphocyte subsets, and specific antibody responses. Variants were classified according to ACMG criteria, and genotype–phenotype correlation was performed. Pathogenic and likely pathogenic variants were considered clinically significant; variants of uncertain significance (VUS) were evaluated within clinical context.

Among 71 patients with evaluable genotype–phenotype correlation, 30 (42.3%) had clinically significant variants. Of these, 66.7% were pathogenic/likely pathogenic and 33.3% were VUS with supportive clinical correlation. Clinically significant genetic findings were significantly associated with autoinflammatory manifestations (p=0.031), lymphopenia (p=0.013), and hypogammaglobulinemia (p=0.041).

Immune dysregulation features and marked immunological abnormalities significantly increase the likelihood of identifying clinically meaningful genetic variants in suspected IEIs. Incorporating these parameters alongside infection history may improve patient selection for genetic testing and enhance diagnostic efficiency.