Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis
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Published on: February 2, 2018
Gen Lu1, Zheng-de Xie, Kun-ling Shen
1Department of Virology Laboratory, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Insights
This study investigated perforin gene (PRF1) mutations in Chinese pediatric patients with hemophagocytic lymphohistiocytosis (HLH). Three heterozygous mutations were identified, with two novel mutations found exclusively in Chinese patients, aiding HLH diagnosis.
Area of Science:
- Genetics
- Pediatric Hematology
- Immunology
Background:
- Germline perforin gene (PRF1) mutations are linked to hemophagocytic lymphohistiocytosis (HLH).
- Limited data exists on PRF1 mutation prevalence in Chinese pediatric HLH patients.
Purpose of the Study:
- To determine the prevalence of PRF1 mutations and sequence variations in Chinese pediatric HLH patients.
- To establish genotype-phenotype correlations for PRF1 mutations in this population.
Main Methods:
- Polymerase chain reaction (PCR) and sequencing of PRF1 coding exons and flanking introns.
- Analysis of 30 pediatric HLH patients and 50 healthy controls.
Main Results:
- Three heterozygous missense mutations (C102F, S108N, T450M) identified in three patients, absent in controls.
- One patient presented compound heterozygous mutations (S108N, T450M) with familial HLH type 2 (FHL2).
- Novel mutations C102F and S108N were exclusively found in Chinese patients.
Conclusions:
- Identified three novel heterozygous missense mutations in PRF1 in Chinese pediatric HLH patients.
- Two mutations (C102F, S108N) are specific to Chinese populations, aiding diagnostic evaluation.
- Primary HLH should be suspected in patients without a familial history, even outside typical age ranges.
Background:
Recent studies have reported germline mutations in the perforin gene (PRF1) in some types of hemophagocytic lymphohistiocytosis (HLH). However, the prevalence of PRF1 mutations in HLH in Chinese pediatric patients has not been extensively studied. The aim of this study was to investigate the prevalence of mutations and sequence variations in the PRF1 gene in Chinese pediatric patients with HLH.
Methods:
Polymerase chain reaction (PCR) was performed with five pairs of primers for the coding exons and the flanking intron sequences of PRF1. Sequencing of PCR products was subsequently applied in 30 pediatric patients with HLH and in 50 controls.
Results:
Three heterozygous mutations in a coding region were found, which resulted in amino acid changes (C102F, S108N and T450M) in three patients. These mutations were not detected in control subjects. One patient had compound heterozygous mutations (S108N and T450M) in PRF1 as the background defect, and documented familial HLH type 2 (FHL2). One synonymous sequence variant (Q540Q) was observed in one patient but not in the controls. Two SNPs (A274A, H300H) in the coding region were detected in HLH patients and controls, but without differences in the heterozygosity rate between the two groups (P > 0.05 for all comparisons).
Conclusions:
We have identified three patients with three heterozygous missense mutations in PRF1; two of those three mutations (C102F and S108N) have so far been found only from Chinese patients. These findings are useful in evaluating the prevalence of PRF1 mutations in Chinese pediatric patients with HLH, and to correlate their genotype with phenotype. Some patients without familial history probably have primary HLH, which should be suspected even beyond the usual age range.
