title: Search for the potential "second-hit" mechanism underlying the onset of familial hemophagocytic lymphohistiocytosis type 2 by whole-exome sequencing analysis.
abstract: 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.
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Gao
authors.affiliation: BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, People's Republic of China; BGI-Shenzhen, Shenzhen, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Dang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: BGI-Shenzhen, Shenzhen, People's Republic of China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: BGI-Shenzhen, Shenzhen, People's Republic of China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tongjuan
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: jiawei@tjh.tjmu.edu.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: jfzhou@tjh.tjmu.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D015820:Cadherins / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000235:genetics; D059472:Exome; D005260:Female; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D054353:Perforin / Q000235:genetics*; D000091363:Protocadherins
chemical_list: D015820:Cadherins; C438604:PCDH18 protein, human; C510468:PRF1 protein, human; D000091363:Protocadherins; D054353:Perforin