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

backgroundX-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

resultsIn 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.

conclusionsThis 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.