Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

Frontiers in Immunology

Immunology

Amir Hamzah Abdul Latiff¹  Intan Hakimah Ismail²  Saharuddin Bin Mohamad³  Charlotte Sundaraj⁴  Chong Ming Choo⁵  Sharifah Adlena Syed Mohamed⁶  Sandeep Singh Gill⁷  Kwai Cheng Chan⁸  Kah Kee Tan⁹  Asiah Kassim^1,10  Lokman Mohd Noh^1,10  Nazatul Haslina Ramly^1,10  Chai Teng Chear^1,11  Mohd Farid Baharin^1,11  Amelia Suhana Zamri^1,11  Adiratna Mat Ripen^1,11  Sharifah Nurul Husna Syed Yahya^1,11 

[1] Allergy and Immunology Centre, Pantai Hospital, Kuala Lumpur, Malaysia;Clinical Immunology Unit, Department of Paediatrics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia;Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia;Centre of Research in Systems Biology, Structural Bioinformatics and Human Digital Imaging (CRYSTAL), Universiti Malaya, Kuala Lumpur, Malaysia;Pediatric Department, Hospital Putrajaya, Ministry of Health, Putrajaya, Malaysia;Pediatric Department, Hospital Sultan Abdul Halim, Ministry of Health, Sungai Petani, Kedah, Malaysia;Pediatric Department, Hospital Sultanah Aminah, Ministry of Health, Johor Bahru, Johor, Malaysia;Pediatric Department, Hospital Wanita Dan Kanak-Kanak Sabah, Ministry of Health, Kota Kinabalu, Sabah, Malaysia;Pediatric Department, Penang General Hospital, Ministry of Health, George Town, Penang, Malaysia;Pediatric Department, Perdana University and Royal College of Surgeons in Ireland (PURCSI), School of Medicine, Perdana University, Kuala Lumpur, Malaysia;Pediatric Department, Tunku Azizah Hospital (Women and Children Hospital Kuala Lumpur), Ministry of Health, Kuala Lumpur, Malaysia;Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia;

关键词: X-linked agammaglobulinemia;    XLA;    Bruton’s tyrosine kinase;    BTK protein;    BTK mutation;    de novo;    COVID-19;   

DOI  :  10.3389/fimmu.2023.1252765

 received in 2023-07-04, accepted in 2023-09-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundBruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.ResultsTwenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.ConclusionThis report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

【 授权许可】

Unknown   
Copyright © 2023 Chear, Ismail, Chan, Noh, Kassim, Latiff, Gill, Ramly, Tan, Sundaraj, Choo, Mohamed, Baharin, Zamri, Yahya, Mohamad and Ripen