The phenotypic spectrum of syndromic optic atrophy associated with variants in WFS1: with reclassification of p.Val606Gly as a likely benign variant

Abstract

ABSTRACT Introduction Wolfram syndrome due to bi-allelic variants in WFS1 and mono-allelic Wolfram-like syndrome have variable ocular and syndromic associations. In this report, eight patients are described. Methods A retrospective observational case series with detailed ophthalmic and systemic phenotyping, optical coherence tomography (OCT), and neuroimaging. Molecular investigations included gene panel and targeted Sanger sequencing. Results Eight patients (six female, two male) from six families were diagnosed with optic atrophy at a mean age of 15.5 ± 6.2 years (range 8–23) with mean follow-up of 3.2 ± 3.4 years (range 1.5–12.1). Three were asymptomatic. Mean presenting visual acuity was 0.31 ± 0.26 logMAR (Snellen equivalent 20/40). Diabetes mellitus was present in five patients (detected after screening in one), sensorineural hearing loss in five and diabetes insipidus in one. Other systemic features included psychiatric disorders in four patients and bladder dysfunction in three patients. OCT demonstrated marked nerve fiber layer loss in all patients. In dominant disease, macular OCT demonstrated a linear splitting abnormality of the outer plexiform layer (OPL) not found in recessive disease. Three novel variants in WFS1 were identified. After identification of the p.Val606Gly variant in three Māori patients including one with cone-rod retinal dystrophy, a reference database of 80 Māori/Pasifika patients with retinal dystrophy/optic atrophy was interrogated. This identified the variant in 10 patients with disease attributed to other genes. Conclusions In Wolfram syndrome, systemic features are variable. Pathognomonic OPL lamination is associated with dominant disease. Early recognition of potentially syndromic optic atrophy allows prompt diagnosis of unrecognized diabetes mellitus.