Autosomal dominant pathogenic variants in the WFS1 gene can cause a broad spectrum of 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, 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 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 WFS1-related disorders by reviewing clinical data from patients with autosomal dominant pathogenic WFS1 variants. 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. Eleven participants with autosomal dominant WFS1 variants meeting these criteria were identified. The 11 cases included five distinct autosomal dominant WFS1 variants: c.923C>G (p.Ser308Cys), c.2051C>T (p.Ala684Val), c.2389G>T (p.Asp797Tyr), c.2456A>C (p.Gln819Pro), and c.2590G>A (p.Glu864Lys). Among these, the p.Gln819Pro variant has not been previously reported in the literature. The median age of optic atrophy diagnosis was 10 years (quartiles: 6.0 and 19.0 years). Visual acuity did not significantly differ between the left (OS) and right (OD) eyes (p = 0.8901). The least square best-corrected visual acuity (BCVA) mean for the right eye was 0.2114 ± 0.01903 and for the left eye, 0.2153 ± 0.01903. Age was not significantly related to best eye BCVA (p = 0.9196), with an estimated change of -0.0002 (95% CI [-0.003, 0.003]) per year. Patient age was also not correlated with binocular BCVA (p = 0.5994), with an estimated change of 0.00075 (95% CI [-0.0021, 0.0036]) per year. Mean retinal nerve fiber layer (RNFL) thickness was not significantly related to age (p = 0.1604), with an estimated annual change of 0.1486 (95% CI [-0.659, 0.363]). However, removing an influential outlier resulted in a significant relationship between RNFL thickness and age (p = 0.0160), with an estimated change of 0.2114 (95% CI [0.045, 0.377]) per year. Hearing loss diagnoses occurred at a median age of 2.0 years (quartiles: 1.5 and 2.0 years). All participants used hearing aids (11/11); six (6/11) had cochlear implants, while three (3/11) used external hearing aids. The median time between hearing loss diagnosis and hearing aid use was 4.0 years (quartiles: 2.5 and 8.0 years). This study contributes to the growing understanding of WFS1-related disorders caused by autosomal dominant WFS1 variants. In particular, it highlights two clinical phenotypes of a novel WFS1 variant and provides valuable insights into the progression of optic nerve atrophy and hearing loss management.

Syndromic genetic disorders affecting vision can also cause hearing loss, and Usher syndrome is by far the most common etiology. However, many other conditions can present dual sensory impairment. Accurate diagnosis is essential for providing patients with genetic counseling, prognostic information, and appropriate resources. This study aimed to describe the genetic profile of combined inherited deaf-blindness in Portugal. This was a cross-sectional study conducted at a tertiary hospital in Portugal. Patients were identified through the national, web-based inherited retinal dystrophies registry (IRD-PT, retina.com.pt). Demographics, clinical, and genetic data were retrieved from individual patient records. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for solved cases. Eighty-four patients (58.3% males; mean age 40.0 ± 17.9 years) from 71 families were included. Usher syndrome was the most frequent etiology (71.4%) followed by Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome (6.0%), Autosomal dominant optic atrophy plus (4.8%) and cone-rod dystrophy and hearing loss (4.8%). Other less frequent etiologies included Alport syndrome (2.4%), Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (2.4%), Heimler syndrome (2.4%), Senior-Loken syndrome (1.2%), Waardenburg syndrome (1.2%), Maternally inherited diabetes and deafness (1.2%), and Stickler syndrome (1.2%). The overall diagnostic yield of deleterious variants in our deaf-blind cohort was 73.2%. A total of 55 genetic variants were identified across 16 different genes; 11 of these variants are novel and herein reported for the first time. This is the first study to describe the genetic profile of patients with dual sensory impairment in Portugal, highlighting the genetic heterogeneity associated with inherited deaf-blindness. Usher syndrome was the most prevalent cause in this cohort. Nevertheless, several other less frequent causes must also be considered. This study showed a high diagnostic yield and reported 11 novel genetic variants, thereby contributing to expand the mutational spectrum of these conditions.

The multicenter NIH-funded Undiagnosed Diseases Network (UDN) exists to diagnose puzzling and newly discovered conditions. We report the UDN's assistance in diagnosing perplexing ocular disorders along with 6 case illustrations. Retrospective Interventional Case Series. Participants with ocular phenotypes who had applied and were accepted into the UDN with detailed supporting letters written by ophthalmologists or other clinicians when clinically indicated genetic and laboratory testing results were not diagnostic. Human Phenotype Ontology Codes were used to identify and categorize subjects with ocular phenotypes. Advanced genomic technologies (exome, genome, mitochondrial and RNA sequencing, X-inactivation analysis, immunoblot analysis) were available for diagnoses. Proportion of cases solved by the UDN in subjects manifesting an ophthalmic component of their undiagnosed disorder. The national UDN diagnostic rate for subjects with an eye phenotype was 40.2% (452 of 1123); the diagnostic rate for the other subjects (without an eye) phenotype was 27.8% (276 of 992). In univariate analysis, having an eye phenotype was significantly associated with receiving a diagnosis (odds ratio [OR] = 1.75; CI = 1.45-2.10; P = 2.28e-09). Of 58 eye diagnosed cases/104 total diagnosed cases at the Vanderbilt UDN site, 6 will be discussed more fully. Vanderbilt UDN cases include an autosomal dominant glaucoma with a variant in TEK/TIE2; a de novo heterozygous variant in PRPS1 causing microcornea and glaucoma with skewed X-inactivation affecting a female; a homozygous variant in NADK2 causing optic nerve atrophy; autosomal recessive variants in EPG5 resulting in optic nerve atrophy and cone-rod dystrophy; and a rare de novo variant in COG4 causing a cataract/ retinitis pigmentosa/ nystagmus phenotype. EPG5 and COG4 are not present on inherited retinal disease panels. The UDN is a national resource available to increase solving undiagnosed diseases including those with ocular phenotypes, facilitate research on undiagnosed diseases, and create a collaboration to improve care options for patients with undiagnosed diseases. Clinicians including ophthalmologists can collaborate with the UDN to solve challenging ocular mysteries using genomic technologies.

Dominant optic atrophy (DOA) is an inherited optic neuropathy caused by mutations of the OPA1 gene. Patients with DOA have a gradual loss of vision that is often detected in early life. While most cases stabilize at around a decimal best-corrected visual acuity (BCVA) of 0.1, some show mild impairments without visual field abnormalities. This then makes the diagnosis of DOA difficult. We report our longitudinal findings of a 56-year-old man with autosomal dominant DOA whose visual functions remained relatively good and genetic testing was needed for the diagnosis of DOA. The patient was first examined 7 years earlier when he was 49-year-old at the Saitama Medical University Hospital. His major complaint was blurred vision. He had no medical or family history of ocular disorders, and his decimal BCVA was 1.0 (Snellen 20/20) in both eyes (OU). The intraocular pressure (IOP) was 13.7 mmHg in the right eye and 14.0 mmHg in the left eye. Slit-lamp examination revealed mild cataracts OU, and fundus examination showed temporal pallor of the optic discs OU. Humphrey visual field analyzer (HFA) standard 30 - 2 white-on-white perimetry indicated that the sensitivity was not reduced. Five years later, the patient returned for further examination because his vision had worsened. The decimal BCVA was 0.8 in the right eye and 0.6 in the left eye, and the IOP was within normal limits OU. The critical fusion frequency (CFF) was 30 Hz in the right eye and 31 Hz (normal values > 39 Hz) in the left eye. Slit-lamp examination and ophthalmoscopy showed no intraocular changes. Optical coherence tomography (OCT) showed a thinning of the retinal nerve fiber layer temporal to the optic disc. The contrast sensitivity was slightly decreased in both eyes, and the Panel D-15 color vision test was normal. Goldmann visual field testing with HFA SITA standard 10 - 2 and 24 - 2 white-on-white perimetry showed no obvious scotomas. However, HFA SITA standard 24 - 2 blue-on-yellow perimetry showed a diffuse decrease of sensitivity. Full-field and focal macular electroretinograms (ERGs) were normal in both eyes. Genetic testing was performed with the patient's consent, and next generation sequencing analysis identified a new heterozygous c.2331+2T>G variant in the OPA1 gene (NM_130837.3). At the final follow-up examination at age 55 years, the decimal BCVA was still relatively good at 0.8 in the right eye and 0.6 in the left eye. These findings indicate that relatively good visual function can be maintained until the late middle age in patients with DOA, and genetic testing should be considered when circumpapillary RNFL thinning is observed, even in patients with relatively good visual acuity.

Cerebellar ataxia-deafness-narcolepsy syndrome (ADCA-DN) is a very rare polymorphic subtype of autosomal dominant ataxia type 1 (ADCA type 1). It begins in adulthood, and may also be associated with other variable symptoms as optic atrophy, cataracts, psychosis, depression or sensory neuropathy. We present a family diagnosed from the first generation, its phenotypic description and genetic study. We describe three members of a family with ADCA sydrome. Patient II-2 started at 51 years, with ataxia, tremor, epileptic seizures, cerebellar atrophy, narcolepsy without cataplexy, hearing loss, moderate cognitive impairment. Patient III-1 started at 42 years with narcolepsy with cataplexy, hearing loss and tremor, and patient IV-1 started at 4 years, with mild intellectual disability, and narcolepsy without cataplexy. Genetic test showed a mutation in DNMT1 gene: variant c.1709 C > T; p.Ala570Val in the DNMT1 gene. ADCA syndrome has a variable phenotype in a same family. In our experience, this type of ataxia develops narcolepsy as the first sympton in all three cases, with tremor and cognitive impairment, together with tremor and cognitive impairment. Ataxia, despite being a cardinal symptom, does not appear at the onset in younger patients, and hearing loss also seems to develop over the years. Sensory neuropathy is not present in any of the cases studied.