Spectrum of BTK gene mutations in Vietnamese patients with X-linked agammaglobulinemia.

BACKGROUND: X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency caused by mutations in the Bruton’s tyrosine kinase (BTK) gene, resulting in severely impaired B-cell development and recurrent bacterial infections in children. Although over 2,000 BTK mutations have been reported worldwide, data from Southeast Asia remain limited. METHODS AND RESULTS: In this study, we conducted a comprehensive genetic analysis of the BTK gene in 82 unrelated Vietnamese male patients clinically diagnosed with XLA, using Sanger sequencing of both genomic DNA and cDNA, combined with in-silico pathogenicity prediction tools. Pathogenic BTK mutations were identified in 36 patients (43.9%), involving 35 distinct variants distributed across all functional domains of the BTK protein. Missense mutations were the most common (37.1%), followed by large deletions (25.7%), splice-site mutations (14.3%), nonsense (11.4%), frameshift (8.6%), and in-frame deletions (2.9%). Two novel variants were identified: a nonsense mutation (p.Q343X) in the SH2 domain and a splice-site mutation (IVS17 + 5G > C). All large deletions were detected only at the mRNA level, highlighting the importance of transcript-based analysis in cases where no mutation is found at the genomic level. CONCLUSIONS: This is the first study to characterize the BTK mutation spectrum in Vietnamese XLA patients, contributing novel variants to the global database and underscoring the value of integrative molecular strategies - particularly mRNA analysis - in enhancing early diagnosis and genetic counseling in this population.