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Whole Exome Sequencing for Mutation Screening in Hemophagocytic Lymphohistiocytosis Publisher



Rahmani ES1 ; Fathi M1 ; Abazari MF2 ; Shahraki H3 ; Fellow VZ4, 5 ; Rahimi H6 ; Hosseini A1
Authors
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Authors Affiliations
  1. 1. Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Science, Tehran, Iran
  2. 2. Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
  3. 3. Department of Laboratory Sciences, School of Allied Medical Sciences, Zahedan University of Medical Sciences, Zahedan, Iran
  4. 4. Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Pediatrics, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

Source: Iranian Journal of Pediatric Hematology and Oncology Published:2020


Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is an immune system disorder characterized by uncontrolled hyper-inflammation owing to hypercytokinemia from the activated but ineffective cytotoxic cells. Establishing a correct diagnosis for HLH patients due to the similarity of this disease with other conditions like malignant lymphoma and leukemia and similarity among its two forms is difficult and not always a successful procedure. Besides, the molecular characterization of HLH due to the locus and allelic heterogeneity is a challenging issue. Materials and Methods: In this experimental study, whole exome sequencing (WES) was used for mutation detection in a four-member Iranian family with children suffering from signs and symptoms of HLH disease. Data analysis was performed by using a multi-step in-house WES approach on Linux OS. Result: In this study, a homozygous nucleotide substitution mutation (c.551G>A:p. W184*) was detected in exon number six of the UNC13D gene. W184* drives to a premature stop codon, so produce a truncated protein. This mutation inherited from parents to a four-month female infant with an autosomal recessive pattern. Parents were carrying out the heterozygous form of W184* without any symptoms. The patient showed clinical signs such as fever, diarrhea, hepatosplenomegaly, high level of ferritin, and a positive family history of HLH disease. W184* has a damaging effect on cytotoxic T lymphocytes, and natural killer cells. These two types of immune system cells without a healthy product of the UNC13D gene will be unable to discharge toxic granules into the synaptic space, so the inflammation in the immune response does not disappear. Conclusion: According to this study, WES can be a reliable, fast, and cost-effective approach for the molecular characterization of HLH patients. Plus, WES specific data analysis platform introduced by this study potentially offers a high-speed analysis step. This cost-free platform doesn't require online data submission. © 2020 Shahid Sadoughi University of Medical Sciences.
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