A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis

Abstract

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2).

Case presentation: Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family.

Conclusions: Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

Keywords: Case report; Hemophagocytic Lymphohistiocytosis (HLH); Novel mutation; PRF1.

Fig. 1

a, b, c and d Axial Flair sequences of brain MRI, which reveal numerous variable size and irregular shape hypersignal areas involving cerebral hemispheres, cerebellar hemispheres, pones and cerebral peduncles, mostly located in the corticomedullary junction and deep white matter in favor of HLH CNS involvement

Fig. 2

The proband is a boy with hepatitis and pancytopnea and his parents has consanguineous marriage. NGS results indicate homozygous mutation in PRF1 gene in the proband as visualized using Integrative Genome Viewer (IGV) and using Sanger sequencing presence of the identified heterozygous mutation in PRF1 gene was confirmed in the parents

Fig. 3

Comparative amino acids alignment of perforin protein across all Kingdoms. The W374 residue is highly conserved during evolution. The conserved tryptophan residue is shown in the rectangular box. Protein sequences were obtained from National Center for Biotechnology (NCBI). Symbols: (*)—identical amino acids; (:) — just similar amino acids