AUTHOR=Heinz Johanna L. , Swagemakers Sigrid M. A. , von Hofsten Joanna , Helleberg Marie , Thomsen Michelle M. , De Keukeleere Kerstin , de Boer Joke H. , Ilginis Tomas , Verjans Georges M. G. M. , van Hagen Peter M. , van der Spek Peter J. , Mogensen Trine H. 

TITLE=Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 16 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1253040

DOI=10.3389/fnmol.2023.1253040

ISSN=1662-5099

ABSTRACT=Purpose: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alpha herpesviruses endemic worldwide. Upon primary infec�on, both viruses establish lifelong latency in neurons and reac�vate intermitently to cause a variety of mild to severe diseases. Acute re�nal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infec�on. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying gene�c defect in at least part of ARN cases.We collected blood from 17 pa�ents with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD >0.1% combined with biological filters. Gene modifica�ons rela�ve to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predic�ons and biological relevance.We iden�fied a total of 50 poten�ally disease-causing gene�c variants, including missense, frameshi� and splice site variants and on in-frame dele�on in 16 of the 17 pa�ents. The vast majority of these genes are involved in innate immunity, followed by adap�ve immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was iden�fied in several pa�ents.We propose that the iden�fied variants may contribute to insufficient viral control and ocular disease presenta�on in the pa�ents and serve as a knowledge base and star�ng point for the development of improved diagnos�c, prophylac�c, and therapeu�c applica�ons.