Diagnostic yield and clinical impact of genetic testing in inborn errors of immunity: lessons from a large Turkish...

Inborn errors of immunity (IEI) are inherited disorders with heterogeneous clinical, immunological, and genetic features; genetic testing is now indispensable for accurate diagnosis and treatment planning. This study aimed to evaluate the diagnostic yield, inheritance patterns, and clinical impact of genetic testing on IEIs at a tertiary care center in Turkey over a 10-year period. This retrospective cohort included 1407 patients diagnosed with or followed for IEI between 2010 and 2020 at Ankara University Faculty of Medicine. Clinical, immunologic, and molecular data were analyzed to assess subgroup distribution, genetic testing methods, turnaround times, and the influence of genetic results on diagnosis and treatment. Predominantly antibody deficiencies were the most common IEI subgroup (67.8%), followed by combined T- and B-cell immunodeficiencies (12.2%). Parental consanguinity was present in 32.1% of patients. Genetic testing was performed in 417 patients (29.6%), and pathogenic variants were identified in 325 (77.9% of the tested population), involving 94 different genes. Most variants exhibited autosomal recessive inheritance (71.4%). The diagnostic yield was 66.8% for targeted gene panels and 68.4% for whole-exome sequencing. Turnaround times markedly decreased from 28.1 months in 2010 to 2.3 months in 2020. Genetic findings led to diagnostic or therapeutic modifications in 20.6% of patients, primarily through disease reclassification or personalized treatment adjustments.

Comprehensive clinical and immunological evaluations remain fundamental to accurate genotypic characterization of patients with IEI. To ensure timely and precise diagnosis, genetic analyses should be initiated early and conducted through close collaboration between clinical immunologists and genetic specialists.

• Inborn errors of immunity are clinically and genetically heterogeneous disorders that often require molecular confirmation for accurate diagnosis. • Genetic testing supports individualized management when integrated with detailed clinical and immunological evaluation.

• In this 10-year, large national cohort from Turkey, clinically guided genetic testing achieved a high diagnostic yield and identified pathogenic variants in the majority of tested patients. • Genetic results led to diagnostic or therapeutic modifications in approximately one-fifth of cases, emphasizing the importance of early, coordinated collaboration between clinical immunologists and genetic specialists.