Genetic landscape of a cohort of children with varicella-zoster virus encephalitis, cerebellitis and stroke

Varicella-zoster virus (VZV) is a neurotropic member of the Herpesviridae family which causes varicella in primary infection and zoster during reactivation but in rare cases can lead to severe neurological complications, such as encephalitis. To identify inborn errors of immunity (IEI) and unravel pathways involved in VZV CNS immune responses and pathogenesis, we performed whole exome sequencing on a cohort of 38 children with neurological manifestations, including VZV encephalitis, cerebellitis, or stroke. We identified a total of 46 rare potentially pathogenic variants predicted to be deleterious, including variants in innate antiviral immunity, inflammation, cell stress responses, and autophagy. Collectively these findings represent a knowledge base for further functional studies and provide new insights into the genetic landscape of VZV CNS infections and highlight potential genetic defects that may compromise host defense, enabling new avenues for diagnosis and personalized treatment strategies for VZV CNS infections.