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Search for the potential “second-hit” mechanism underlying the onset of familial hemophagocytic lymphohistiocytosis type 2 by whole-exome sequencing analysis

  • Lili Gao
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Xiao Dang
    Affiliations
    BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, People's Republic of China

    BGI-Shenzhen, Shenzhen, People's Republic of China
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  • Liang Huang
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Li Zhu
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Mingyan Fang
    Affiliations
    BGI-Shenzhen, Shenzhen, People's Republic of China
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  • Jianguo Zhang
    Affiliations
    BGI-Shenzhen, Shenzhen, People's Republic of China
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  • Xun Xu
    Affiliations
    BGI-Shenzhen, Shenzhen, People's Republic of China
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  • Lijun Zhu
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Tongjuan Li
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Lei Zhao
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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  • Jia Wei
    Correspondence
    Reprint requests: Jianfeng Zhou and Jia Wei, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Avenue, Wuhan 430030, People's Republic of China
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for articles by this author
  • Jianfeng Zhou
    Correspondence
    Reprint requests: Jianfeng Zhou and Jia Wei, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Avenue, Wuhan 430030, People's Republic of China
    Affiliations
    Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for articles by this author
Published:December 14, 2015DOI:https://doi.org/10.1016/j.trsl.2015.12.004
      Familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by perforin 1 (PRF1), is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first 2 years of life and has a poor prognosis. Late onset of FHL2 has been sporadically reported, and the mechanism is largely unknown. A newly diagnosed FHL2 patient was detected to have compound mutations in both PRF1 alleles and positive Epstein-Barr virus (EBV) infection. Her brother carried the same mutations and EBV infection status but kept healthy. To search the potential unknown mechanisms, we performed whole-exome sequencing analysis. The patient and her asymptomatic brother carried the same heterozygous missense (c.916G>A) and frameshift mutation (c.65delC) in PRF1. Germline mutation analysis demonstrated that only the proband was exclusively detected with a homozygous missense mutation (S1006L) in the PCDH18 gene, whereas others were found to have a heterozygous mutation (S1006L) of PCDH18. The calculated stability (free energy) changes showed that the mutation of PCDH18 mainly destabilized the protein structure. Furthermore, the mutation (S1006L) could lessen the PCDH18-induced inhibition of target cell activation and reduce the apoptosis of T lymphocytes. This study is the first to perform whole-exome sequencing analysis to search the potential “second-hit” mechanism that underlies the onset of FHL2. A novel type of compound heterozygous mutation has been found in PRF1. The detection of the homozygous germline mutation in PCDH18 strongly argues that the presence of a “second” germline mutation besides the PRF1 gene might be potentially an important mechanism for triggering the onset of FHL2.

      Abbreviations:

      APC (antigen-presenting cell), CTLs (cytotoxic T cells), EBV (Epstein-Barr virus), FHL (familial hemophagocytic lymphohistiocytosis), H&E (hematoxylin and eosin), HLH (hemophagocytic lymphohistiocytosis), PBMCs (peripheral blood mononuclear cells), PBS (phosphate balanced solution), PRF1 (perforin 1), rIL-2 (recombinant interleukin 2), RT-PCR (reverse transcription–polymerase chain reaction), SE (standard error)
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