Abstract
Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies.