Inborn errors of immunity (IEIs) are rare genetic disorders caused by pathogenic germline variants affecting immune function. They lead to increased susceptibility to infections, autoimmunity, autoinflammatory syndromes, bone marrow failure, and malignancies. Over 500 IEI types are known, and their clinical and molecular heterogeneity poses major diagnostic challenges, often delaying diagnosis and treatment.
This study was conducted at a Rare Disease Reference Center in Southern Brazil, combining retrospective and prospective data collection from 2023 to 2025, through a medical records review and informed consent sign. To date, 77 patients with suspected IEIs have been enrolled, and recruitment of new participants remains ongoing, following informed consent. Genetic analyses were performed in a research setting, using exome sequencing, gene panels, or single-gene analysis, according to clinical indication and test availability.
Among the patients, 70% (n = 54) were male, with a median age at symptom onset of 36 months (range: 0–915). IEI-related symptoms occurred in 46% within the first two years of life. However, the median age at genetic investigation was 10.4 years, highlighting a diagnostic delay of 7–8 years. Exome sequencing was performed in 57%, gene panels in 35%, and single-gene testing in 2.6%. Genetic results were available for 36% (n = 28/54), with a diagnostic yield of 50% (n = 14/28). Among positive findings, the most common category was congenital phagocyte defects (36%), followed by combined cellular and humoral immunodeficiencies (28%), syndromic combined immunodeficiencies (21%), intrinsic/innate immunity defects (7%), and immune dysregulation disorders (7%).
Despite early symptom onset, genetic testing was delayed, highlighting a significant diagnostic gap. Contributing factors include low medical awareness, challenges in referral to specialized centers, and limited test access. Establishing specialized IEI clinics is essential for early diagnosis, improved care, family support, and ultimately improve clinical outcomes and quality of life.
