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 the WFS1 gene can cause a broad spectrum of Autosomal dominant WFS1 -related disorders. These disorders present with a range of phenotypic manifestations, including isolated low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, isolated diabetes mellitus, and early-onset cataracts. In general, Autosomal dominant WFS1 -related disorders represent a milder spectrum of conditions linked to pathogenic WFS1 variants, except for Hattersley-Urano syndrome, which is characterized by early-onset diabetes mellitus, optic nerve atrophy, cataracts, hypotonia, intellectual disability, and developmental delay. By contrast, autosomal recessive WFS1 variants result in Wolfram Syndrome type 1, a rare neurodegenerative disorder characterized by early-onset diabetes mellitus, optic nerve atrophy, arginine vasopressin deficiency, hearing loss, and cerebellar and brainstem atrophy. Although Autosomal dominant WFS1 -related disorders have been increasingly recognized, additional data are needed to understand their clinical progression and long-term outcomes. Our study aims to expand knowledge on the severity and progression of Autosomal dominant WFS1 -related disorders by reviewing clinical data from patients with autosomal dominant pathogenic WFS1 variants. Approach: We obtained clinical data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. We included participants with autosomal dominant WFS1 pathogenic variants who were diagnosed with optic nerve atrophy and sensorineural hearing loss. Fifteen participants with autosomal dominant WFS1 variants meeting these criteria were identified. 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. The median age of optic atrophy diagnosis was 10 years (lower and upper quartiles: 7.0 and 17.5). Current age of patients is not significantly related to longitudinal mean BCVA of both eyes (p=0.3185), with an estimated slope of 0.00019 logMAR/year (95% CI, -0.0019 to 0.0057). Using all data, current age was not significantly related to mean RNFL (p=0.1547), with a slope estimate of 0.1513 mm/year (95% CI [-0.0612, 0.3637]). Of the eight patients with optical computed tomography (OCT) scans, six had evident outer plexiform retinal layer lamination – a unique feature of Autosomal dominant WFS1 -related disorders. Hearing loss diagnoses occurred at a median age of 2.0 years (quartiles: 1.0 and 2.5). All participants use hearing aids (15/15); eight (8/15) have bilateral cochlear implants, while four (4/15) use bilateral external hearing aids, one patient has a cochlear implant and external aid (1/15). The median time between hearing loss diagnosis and first use of hearing aids was 2.2 years (quartiles: 1.6 and 4.6). Conclusion: This study highlights that patients with Autosomal dominant WFS1 -related disorders experience hearing loss early in life, and optic atrophy onset in late childhood with visual acuity and mean RNFL thickness that do not change significantly with age. It also supports that OPL lamination is a highly characteristic finding in Autosomal dominant WFS1 -related disorders. Furthermore, we detail four clinical presentations of three novel WFS1 variants.