Natural history of 15 patients with autosomal dominant WFS1 pathogenic variants associated with sensorineural hearing loss and optic atrophy.

OBJECTIVE: Autosomal dominant pathogenic variants in WFS1 cause a spectrum of disorders with phenotypic manifestations including low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, non-syndromic diabetes mellitus, and early-onset cataracts. These conditions are generally milder than autosomal recessive Wolfram syndrome, except for Hattersley-Urano syndrome. Despite growing recognition of these disorders, data on clinical progression and long-term outcomes remain limited. This study aims to expand knowledge on disease severity and progression in autosomal dominant WFS1-related disorders. APPROACH: Clinical data were obtained from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. Fifteen participants with autosomal dominant WFS1 pathogenic variants presenting with both optic nerve atrophy and sensorineural hearing loss were included. RESULTS: The 15 cases included seven distinct autosomal dominant WFS1 variants: c.923C>G (p.Ser308Cys), c.2051C>T (p.Ala684Val), c.2389G>T (p.Asp797Tyr), c.2402A>G (p.Asp801Gly), c.2456A>C (p.Gln819Pro), c.2492G>C (p.Gly831Ala), and c.2590G>A (p.Glu864Lys). Among these, the c.2402A>G, c.2456A>C, and c.2492G>C variants have not been previously published. Median age at optic atrophy diagnosis was 10 years. Visual acuity and RNFL thickness did not change significantly with age. Of eight patients with Optical coherence tomography (OCT) scans, six showed outer plexiform layer (OPL) lamination, a characteristic feature of this disorder. Hearing loss was diagnosed at a median age of 2.0 years; all 15 participants use hearing aids, and eight have bilateral cochlear implants. CONCLUSION: Patients with autosomal dominant WFS1-related disorders experience early-onset hearing loss and late-childhood optic atrophy, with stable visual acuity and RNFL thickness over time. OPL lamination is a highly characteristic finding, and three novel variants with four clinical presentations are described.