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CASE REPORT article

Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1504816

Case Report: A novel de novo germline loss-of-function mutation in the STAT1 transactivation domain in two Chinese siblings with the elder sibling presenting with multifocal Bacillus Calmette-Guerin (BCG) osteomyelitis

Provisionally accepted
Qin Ying Lim Qin Ying Lim 1,2Daniel Leung Daniel Leung 2Crystal K Lam Crystal K Lam 3Xingtian Yang Xingtian Yang 2Kai N Cheong Kai N Cheong 2,4Andrew KH Yik Andrew KH Yik 2Jing Yang Jing Yang 2Koon-Wing Chan Koon-Wing Chan 2Pamela PW Lee Pamela PW Lee 1,2,4,5Miyuki Tsumura Miyuki Tsumura 6Elaine YL Au Elaine YL Au 3Jaime S Rosa Duque Jaime S Rosa Duque 1,2,4*Satoshi Okada Satoshi Okada 6*Yu Lung Lau Yu Lung Lau 1,2,4
  • 1 Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, Hong Kong, SAR China
  • 2 Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
  • 3 Division of Clinical Immunology, Department of Pathology, Queen Mary Hospital, Hong Kong Special Administrative Region, Hong Kong, SAR China
  • 4 Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, Hong Kong, SAR China
  • 5 Department of Pediatrics, Shenzhen Hospital, The University of Hong Kong, Shenzhen, Guangdong, China
  • 6 Department of Paediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

The final, formatted version of the article will be published soon.

    Signal transducer and activator of transcription 1 (STAT1) gene mutations have broad clinical phenotypes, classified by the inheritance pattern and functional state. Individuals with autosomal dominant STAT1 deficiency are more susceptible to intracellular bacteria, the hallmark of which is Mendelian susceptibility to mycobacterial diseases (MSMD) that are associated with increased risks of invasive disease by weakly virulent mycobacteria. We report a novel de novo heterozygous missense mutation in exon 23 of the STAT1 gene (NM_007315.4):c.2129C>T(p.Ser710Phe) (S710F), located in the transactivation domain (TAD) for two Chinese siblings, whereby the index patient presented with multifocal osteomyelitis after Bacillus Calmette-Guerin (BCG) vaccine, while the younger sibling was spared the infection as BCG vaccination was withheld at birth. STAT1 loss-of-function was confirmed by the gamma-activated sequence reporter assay, representing the first loss-of-function mutation in the TAD of the STAT1 gene. Both parents did not have the same mutation, and this finding is suggestive of gonadal mosaicism.

    Keywords: STAT1 loss-of-function, BCG osteomyelitis, Mendelian susceptibility to mycobacterial diseases, Germline mosaicism, case report

    Received: 01 Oct 2024; Accepted: 09 Dec 2024.

    Copyright: © 2024 Lim, Leung, Lam, Yang, Cheong, Yik, Yang, Chan, Lee, Tsumura, Au, Rosa Duque, Okada and Lau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Jaime S Rosa Duque, Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
    Satoshi Okada, Department of Paediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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