Host genetic variability, particularly involving inborn errors of immunity (IEI), has emerged as a critical determinant of interindividual differences in COVID-19 severity, yet comprehensive genomic characterization of IEI-related variants in admixed Latin American populations remains scarce. To characterize rare pathogenic variants in IEI-related genes among previously healthy young Brazilian adults with severe COVID-19 and to evaluate their association with clinical outcomes and genetic ancestry. We performed whole-genome sequencing on 161 unrelated Brazilian adults aged 18-60 years, without comorbidities, who required intensive care unit admission for severe COVID-19 across six Brazilian states. A targeted analysis of 504 IEI-related genes, defined by the 2024 International Union of Immunological Societies (IUIS) classification, was conducted using a stringent variant filtering pipeline incorporating predicted functional impact, population rarity (minor allele frequency ≤ 0.01 in gnomAD v4.1 and the 1000 Genomes Project), Combined Annotation-Dependent Depletion (CADD) scores > 15, Gene Damage Index < 13.84, and pathogenicity classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Ancestry proportions were estimated using ADMIXTURE (K = 3). We identified 49 unique pathogenic or likely pathogenic (P/LP) variants across 37 IEI genes in 45 patients (27.9% of the cohort), comprising 21 pathogenic (42.9%) and 28 likely pathogenic (57.1%) variants. The most frequent molecular consequences were missense variants (n = 21, 42.9%), followed by frameshift (n = 10, 20.4%), stop-gained (n = 9, 18.4%), and splice-site variants (n = 8, 16.3%). Complement deficiencies constituted the largest IEI category (8 variants, 16.3%), followed by phagocyte defects and bone marrow failure (7 variants each, 14.3%). The most frequently affected gene was CFTR (n = 6 variants), and the PMS2 c.2186_2187del frameshift variant was shared among eight unrelated patients, representing the most recurrent variant in the cohort. Seven variants were entirely absent from gnomAD global and Americas databases, including novel variants in FANCA, MVK, TPP2, ELANE, TGFBR1, TCIRG1, and CARD9. Notably, the MVK c.658A > T nonsense variant was identified in two unrelated patients despite its complete absence from reference databases. Ancestry analysis revealed a tri-hybrid profile (European 60.5%, African 26.6%, Amerindian 13.0%), with no significant association between IEI variant carrier status and any ancestry component (all p > 0.6). Strikingly, IEI variant carriers exhibited significantly lower rates of circulatory shock (20.0% vs. 52.6%; OR = 0.23, 95% CI 0.10-0.51, p < 0.001) and acute respiratory distress syndrome (40.0% vs. 61.2%; OR = 0.42, 95% CI 0.21-0.85, p = 0.021) compared to non-carriers, alongside higher absolute lymphocyte counts (median 1,055 vs. 866 cells/mm3, p = 0.024). In-hospital mortality did not differ significantly between groups (11.1% vs. 24.1%; OR = 0.39, 95% CI 0.14-1.09, p = 0.082). These findings demonstrate that rare IEI-related germline variants are present in a substantial proportion of previously healthy young adults with life-threatening COVID-19 and suggest that IEI-associated immune attenuation may modulate disease phenotype by dampening hyperinflammatory responses-potentially protecting against cytokine storm-driven complications while still predisposing to severe illness through impaired viral clearance. This study underscores the relevance of host immunogenetic profiling in admixed populations for understanding the pathophysiology of severe infectious diseases.
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