WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma

Abstract

WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision loss. On exam visual acuities were at 20/100 level, had a tritan color defect and showed central arcuate visual field defects on visual field testing. Enlarged cup-to-disk ratios with normal intraocular pressures were associated with severe thinning of the ganglion cell layer (GCL) and retinal nerve fiber layer consistent with a clinical diagnosis of normal tension glaucoma. Full-field electroretinograms revealed a severe inner retinal dysfunction with reduced amplitudes and remarkably delayed timings of the b-wave, but preserved photoreceptor (a-wave) function. The pattern described herein recapitulates some of the findings of an animal model of WDR36-associated POAG and suggests a mechanism of disease that involves a retina-wide inner retinal dysfunction and neurodegeneration beyond the GCL. Further detailed structural and functional characterizations of patients with a pathogenic variant in the WDR36 gene are required to confirm these findings.

Next-generation sequencing-based gene panel tests for the detection of rare variants and hypomorphic alleles associated with primary open-angle glaucoma

“…Monemi et al demonstrated WDR36 gene expression in the lens, iris, ciliary muscles, ciliary body, trabecular meshwork, retina, and optic nerve by RT-PCR with four pathogenic variants (p.N355S, p.A449T, p.R529Q and p.D658G) associated with adult-onset POAG with implications for both high-and low-pressure glaucoma [64]. In our study, we detected the variant p.E298N in the WDR36 gene in a patient with severe LTG, whose phenotype was very similar to another reported LTG patient with a variant (p.N355S) in the WDR36 gene [58]. Some of the patients carrying rare variants (patient 1 and patient 8) presented with thin pachymetry, which is a known endophenotypic trait that increases the degree of severity of the glaucoma cases, whether this trait has been directly linked to the variant described or is a consequence of other genetic/epigenetic influences still has to be elucidated.…”

“…Similarly, contradictory results are reported for the association of pathogenic variants in the WDR36 gene with glaucoma. Whereas several studies have indicated that genetic variants in WDR36 gene are contributing risk factors for glaucoma progression and severity [54][55][56][57][58], recent clinical trials and meta-analyses have suggested a lack of effect [59][60][61]. However, it is known that this gene has a connection to glaucoma susceptibility and even to retinal homeostasis [62,63].…”

Molecular genetics of primary open-angle glaucoma

“…WDR36 is expressed in a variety of tissues, including the ciliary body, iris, lens, optic nerve, retina, sclera, and trabecular meshwork. [ 119 ] In 2005, WDR36 was linked to POAG pathogenesis. In that study, four variations were identified in the WDR36 gene (c.1064A > G; c.1345G > A; c.1586G > A; c.1973A > G), and these variations covered approximately 6% of the POAG patients.…”