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

Area of Science:

• Immunology
• Genetics
• Neonatal Medicine

Background:

• Neonatal herpes simplex virus (HSV) infection can be fatal, especially disseminated forms.
• Susceptibility to herpes simplex encephalitis (HSE) in adults/children suggests inborn errors in toll-like receptor 3 (TLR3) signaling.
• The genetic basis for neonatal HSV susceptibility, including disseminated disease, is largely unknown.

Purpose of the Study:

• To investigate the genetic basis of susceptibility to neonatal HSV infections.
• To identify variants in known HSE-susceptible genes and other immune-related genes in newborns with HSV.
• To test the hypothesis that genetic defects contribute to severe neonatal HSV outcomes.

Main Methods:

• Unbiased exome sequencing was performed on 10 newborns with disseminated, HSE, or skin, eyes, and mouth HSV disease.
• Potential impact of identified variants on gene function was assessed using American College of Medical Genetics and Genomics guidelines.
• Rare and potentially deleterious variants were identified in genes critical for immune response to HSV.

Main Results:

• Deleterious/potentially deleterious rare variants were found in HSE-related genes: IRF3, TLR3, TRAF3, STAT1, and DBR1.
• Novel rare variants were identified in other immunodeficiency or HSV-related immune genes: GRB2, RAG2, PRF1, C6, C7, and MSR1.
• A novel stop variant in GRB2, crucial for T-lymphocyte responses to HSV, was identified in one infant.

Conclusions:

• Deleterious genetic variants in the TLR3 pathway and anti-HSV immunity genes were identified in neonates with HSV infections.
• These findings suggest a potential genetic predisposition to severe neonatal HSV, including disseminated disease.
• Larger studies with functional analyses are needed to confirm the role of these immune genetic variants in neonatal HSV susceptibility.