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Genetic variation in genes of inborn errors of immunity in children with unexplained encephalitis

Genes & Immunity volume 23, pages 235–239 (2022)Cite this article

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Abstract

Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis’ development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis.

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The authors confirm that the data supporting the finding of this study are available within the article and its Supplementary Material. Raw data supporting the findings are available from the corresponding author upon reasonable request.

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Acknowledgements

Funding was provided in part by NIH K12HD047349 (Kernan), University of Pittsburgh Medical Center Institute of Precision Medicine (Kernan), Children's Neuroscience Institute (Kernan), Brackenridge Fellowship University of Pittsburgh (Malik). DSR was supported by the Children's Neuroscience Institute (Rajan) and Scleroderma Foundation (Rajan).

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Authors and Affiliations

  1. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Devesh Malik

  2. Department of Critical Care Medicine, UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Dennis W. Simon & Kate F. Kernan

  3. Division of Neurology, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Kavita Thakkar & Deepa S. Rajan

Authors
  1. Devesh Malik
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  2. Dennis W. Simon
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  3. Kavita Thakkar
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  4. Deepa S. Rajan
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  5. Kate F. Kernan
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Contributions

All authors contributed to the article and approved the submitted version. KFK and DM designed study, generated and analyzed the data, conceptualized, wrote and edited the manuscript. DWS, DSR, and KT analyzed the data and edited the manuscript.

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Correspondence to Kate F. Kernan.

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The authors declare no competing interests.

Ethical approval

The study was approved by the Institutional Review Board at the University of Pittsburgh (#20010099). Written informed consent was obtained from one or more parents/guardians for each child. Written assent was garnered when the child was able. Written informed consent was obtained for participation in the study, as well as consent for publication of study results.

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Malik, D., Simon, D.W., Thakkar, K. et al. Genetic variation in genes of inborn errors of immunity in children with unexplained encephalitis. Genes Immun 23, 235–239 (2022). https://doi.org/10.1038/s41435-022-00185-5

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