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Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children

Anshul Vagrecha1,2, Mingce Zhang3, Suchitra Acharya1,2

  • 1Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY 11040, USA.

Biology
|March 26, 2022
PubMed

Insights

Genetic mutations in primary hemophagocytic lymphohistiocytosis (pHLH) and DOCK8 genes are linked to multisystem inflammatory syndrome in children (MIS-C). These rare variants may increase susceptibility to MIS-C following SARS-CoV-2 infection.

Area of Science:

  • Immunology
  • Genetics
  • Pediatrics

Background:

  • Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition following SARS-CoV-2 infection.
  • The genetic underpinnings of MIS-C susceptibility remain incompletely understood.

Purpose of the Study:

  • To investigate the role of genetic variations in primary hemophagocytic lymphohistiocytosis (pHLH) and related genes in children diagnosed with MIS-C.
  • To assess the functional impact of identified genetic variants on immune cell function.

Main Methods:

  • Genetic screening of 45 children with MIS-C using a 109-immune-gene panel.
  • Analysis of mutations in pHLH genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) and the DOCK8 gene.
  • In vitro functional assays using NK-92 cells to evaluate the impact of DOCK8 variants on natural killer (NK) cell degranulation and lytic function.

Main Results:

  • Thirty-nine children were diagnosed with MIS-C.
  • 25.4% of MIS-C patients carried rare heterozygous missense mutations in pHLH or DOCK8 genes.
  • Identified DOCK8 variants impaired NK cell degranulation and lytic function in vitro.

Conclusions:

  • Heterozygous mutations in pHLH and DOCK8 genes may represent a genetic risk factor for developing MIS-C after SARS-CoV-2 infection.
  • These findings highlight the importance of genetic predisposition in the pathogenesis of MIS-C.

Keywords:
DOCK8HLHMIS-CVUS

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