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Background <p>X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency caused by mutations in the <i>Bruton’s tyrosine kinase</i> (<i>BTK</i>) gene, resulting in severely impaired B-cell development and recurrent bacterial infections in children. Although over 2,000 <i>BTK</i> mutations have been reported worldwide, data from Southeast Asia remain limited.</p> Methods and results <p>In this study, we conducted a comprehensive genetic analysis of the <i>BTK</i> 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 <i>BTK</i> 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 &gt; 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.</p> Conclusions <p>This is the first study to characterize the <i>BTK</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月23日

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  • Phan Thi Xinh,
  • Ho Quoc Chuong,
  • Hoang Phan Thanh Hien,
  • Huynh Nghia,
  • Phan Nguyen Lien Anh,
  • Hoang Le Phuc,
  • Nguyen Hoang Mai Anh,
  • Nguyen Dinh Van,
  • Hoang Anh Vu

摘要

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.