Rare Genetic Variants in Immune Genes and Neonatal Herpes Simplex Viral Infections

Pediatrics. 2021 Jan;147(1):e20200687. doi: 10.1542/peds.2020-0687. Epub 2020 Dec 18.


Neonatal herpes simplex virus (HSV) infection is a devastating disease with high mortality, particularly when disseminated. Studies in adults and children suggest that susceptibility to herpes simplex encephalitis (HSE) may represent phenotypes for inborn errors in toll-like receptor 3 (TLR3) signaling. However, the genetic basis of susceptibility to neonatal HSV including disseminated disease remains unknown. To test the hypothesis that variants in known HSE-susceptible genes as well as genes mediating HSV immunity will be identified in neonatal HSV, we performed an unbiased exome sequencing study in 10 newborns with disseminated, HSE, and skin, eyes, and mouth disease. Determination of potential impact on function was determined by following American College of Medical Genetics and Genomics guidelines. We identified deleterious and potentially deleterious, rare variants in known HSE-related genes including a stop IRF3 variant (disseminated), nonsynonymous variants in TLR3 and TRAF3 (HSE), STAT1 (skin, eyes, and mouth), and DBR1 (disseminated) in our cohort. Novel and rare variants in other immunodeficiency genes or HSV-related immune genes GRB2, RAG2, PRF1, C6, C7, and MSR1 were found in 4 infants. The variant in GRB2, essential for T-lymphocyte cell responses to HSV, is a novel stop variant not found in public databases. In this pilot study, we identified deleterious or potentially deleterious variants in TLR3 pathway and genes that regulate anti-HSV immunity in neonates with HSV including disseminated disease. Larger, definitive studies incorporating functional analysis of genetic variants are required to validate these data and determine the role of immune genetic variants in neonatal HSV susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Complement C6 / genetics
  • Complement C7 / genetics
  • DNA-Binding Proteins / genetics
  • Exome Sequencing
  • Female
  • GRB2 Adaptor Protein / genetics
  • Genetic Variation*
  • Herpes Simplex / genetics*
  • Humans
  • Infant, Newborn
  • Interferon Regulatory Factor-3 / genetics
  • Male
  • Nuclear Proteins / genetics
  • Perforin / genetics
  • Pilot Projects
  • Pregnancy
  • Pregnancy Complications, Infectious / genetics*
  • RNA Nucleotidyltransferases / genetics
  • STAT1 Transcription Factor / genetics
  • Scavenger Receptors, Class A / genetics
  • TNF Receptor-Associated Factor 3 / genetics
  • Toll-Like Receptor 3 / genetics


  • Complement C6
  • Complement C7
  • DNA-Binding Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • MSR1 protein, human
  • Nuclear Proteins
  • PRF1 protein, human
  • RAG2 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Scavenger Receptors, Class A
  • TLR3 protein, human
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • Toll-Like Receptor 3
  • Perforin
  • Dbr1 protein, human
  • RNA Nucleotidyltransferases

Supplementary concepts

  • Neonatal herpes