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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Downloads (Pure)

Abstract

Purpose: 

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases. 

Methods: 

We collected blood from 17 patients 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 modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance. 

Results

We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.

Discussion: 

We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.

Original languageEnglish
Article number1253040
JournalFrontiers in Molecular Neuroscience
Volume16
DOIs
Publication statusPublished - 25 Oct 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 Heinz, Swagemakers, von Hofsten, Helleberg, Thomsen, De Keukeleere, de Boer, Ilginis, Verjans, van Hagen, van der Spek and Mogensen.

Fingerprint

Dive into the research topics of 'Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants'. Together they form a unique fingerprint.

Cite this