Deciphering the clinical and genetic spectrum of early-onset inborn errors of immunity in a Brazilian pediatric cohort.
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Inborn errors of immunity are a heterogeneous group of rare genetic disorders associated with susceptibility to infections, autoimmunity, allergy, and malignancy. Owing to marked clinical variability, phenotypic overlap, and limited access to specialized diagnostic resources, their diagnosis remains challenging. To investigate the diagnostic contribution of whole-exome sequencing in this setting, we studied 100 Brazilian children up to 4 years of age with early-onset manifestations suggestive of inborn errors of immunity. Exome findings were classified as conclusive diagnoses, suggestive diagnoses, or alternative genetic diagnoses, according to variant pathogenicity and phenotype correlation. The cohort included children from 48 municipalities across Brazil, with a mean age of 16.7 ± 12.9 months at recruitment. A conclusive molecular diagnosis was established in 17% of cases. In this group, 21 disease-causing variants were identified, one-third of which were novel. Thirteen individuals had suggestive genetic findings, whereas five were diagnosed with conditions outside the inborn errors of immunity classification; in this latter group, two-thirds of the variants were novel. The most frequent category among conclusive diagnoses was combined immunodeficiencies with associated features or syndromes. Investigation of probands also led to the identification of 21 additional affected family members. Importantly, the molecular findings had a direct effect on clinical care, including the indication for hematopoietic stem cell transplantation in >50% of index cases with conclusive diagnoses, as well as implications for targeted treatment, genetic counseling, and reproductive planning. These findings demonstrate that whole-exome sequencing is a valuable diagnostic approach in children with early and complex presentations suggestive of inborn errors of immunity, while also contributing to genomic knowledge in an underrepresented population.