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<p>HLH is an infrequent, potentially life-threatening condition. It is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages. Perforin plays a critical role in the lysis of lymphocytes. The PRF1 gene encodes perforin. The PRF1 gene mutations can cause an autosomal recessive form of type 2 familial HLH. This study investigated pathogenic PRF1 mutations in suspected HLH patients in Iran, a country with high consanguinity rates. In this cross-sectional study, the medical profiles of 24 unrelated HLH patients (13 Male and 11 female, mean age 35.25 months) diagnosed using HLH-2004 criteria, who registered at our center, between 2016 and 2019, were reviewed. DNA samples were extracted from patient blood samples and sequenced for the PRF1 gene by Sanger sequencing. The patients’ demographic, clinical, and laboratory characteristics were obtained from their medical records. Among the mutations, the synonymous mutation located at c.822&#xa0;C &gt; T, p.Ala274 = in exon 3 of the PRF1 gene was found in 75% of all patients (41.66% homozygous, 33.33% heterozygous). Additionally, pathogenic missense mutations were identified in 8.33% (2/24) of patients: specifically, c.272&#xa0;C &gt; T (p.Ala91Val) in exon 2 and c.1120T &gt; G (p.Trp374Gly) in exon 3 of the PRF1 gene. Notably, both patients had consanguineous parents and were heterozygous mutation carriers. The c.1120T &gt; G and c.272&#xa0;C &gt; T PRF1 gene mutations are strongly associated with familial HLH type 2. In contrast, the c.822&#xa0;C &gt; T PRF1 gene mutation represents a synonymous mutation in 75% of our cohort. These findings have important implications for genetic counseling and diagnostic approaches in the Iranian population with suspected HLH. Larger, functionally oriented studies that combine next-generation sequencing with perforin assays are required to verify these associations, refine genotype–phenotype correlations, and guide early diagnosis and genetic counselling in this high-consanguinity population.</p>

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The Role of Perforin Gene Mutation in Patients Suspected of Hemophagocytic Lymphohistiocytosis

  • 期刊论文

  • 发表日期：

    2025年9月20日

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  • Mansoureh Shokripour,
  • Bita Pakniat Jahromi,
  • Ahmad Monabati,
  • Golsa Shekarkhar,
  • Nasibeh Sargazi Moghadam,
  • Anita Alenabi

摘要

HLH is an infrequent, potentially life-threatening condition. It is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages. Perforin plays a critical role in the lysis of lymphocytes. The PRF1 gene encodes perforin. The PRF1 gene mutations can cause an autosomal recessive form of type 2 familial HLH. This study investigated pathogenic PRF1 mutations in suspected HLH patients in Iran, a country with high consanguinity rates. In this cross-sectional study, the medical profiles of 24 unrelated HLH patients (13 Male and 11 female, mean age 35.25 months) diagnosed using HLH-2004 criteria, who registered at our center, between 2016 and 2019, were reviewed. DNA samples were extracted from patient blood samples and sequenced for the PRF1 gene by Sanger sequencing. The patients’ demographic, clinical, and laboratory characteristics were obtained from their medical records. Among the mutations, the synonymous mutation located at c.822 C > T, p.Ala274 = in exon 3 of the PRF1 gene was found in 75% of all patients (41.66% homozygous, 33.33% heterozygous). Additionally, pathogenic missense mutations were identified in 8.33% (2/24) of patients: specifically, c.272 C > T (p.Ala91Val) in exon 2 and c.1120T > G (p.Trp374Gly) in exon 3 of the PRF1 gene. Notably, both patients had consanguineous parents and were heterozygous mutation carriers. The c.1120T > G and c.272 C > T PRF1 gene mutations are strongly associated with familial HLH type 2. In contrast, the c.822 C > T PRF1 gene mutation represents a synonymous mutation in 75% of our cohort. These findings have important implications for genetic counseling and diagnostic approaches in the Iranian population with suspected HLH. Larger, functionally oriented studies that combine next-generation sequencing with perforin assays are required to verify these associations, refine genotype–phenotype correlations, and guide early diagnosis and genetic counselling in this high-consanguinity population.