Background: Inherited perforin deficiency is a rare autosomal recessive disorder that causes severe form of hemophagocytic lymphohistiocytosis (FHL2). The main aim of this study was to analyze the nature of gene mutations in a cohort of Indian patients with FHL2 and to utilize this knowledge for genetic counseling and prenatal diagnosis.
Methods: 13 HLH patients with abnormal perforin expression on NK cells by flow cytometry were included in the study. The entire coding region and intronic splice sites of the PRF1 gene were sequenced from the genomic DNA of these patients.
Results: 10 patients from the present series had an early presentation with severe clinical manifestations, while 3 had a delayed onset with unusual presenting features viz Hodgkin's lymphoma, tuberculosis and acute lymphoblastic leukemia. Sequence analysis revealed 11 different mutations (8 novel and 3 previously reported) spread over the entire coding region of PRF1 gene. Missense mutation Trp129Ser in heterozygous state was present in all the 3 patients with a delayed onset of the disease.
Conclusion: A wide heterogeneity was observed in the nature of mutations in Indian FHL2 patients. Molecular characterization of PRF1 gene was not only used in the confirmation of diagnosis but also in genetic counseling and pre-natal diagnosis in affected families.
Keywords: FHL; Genotye–phenotype correlation; Molecular studies; Perforin gene; Pre-natal diagnosis.
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