Recently, a multi-center analysis of a large USH2A patient cohort found different visual outcomes in patients with Usher syndrome compared to NSRP 24. Interestingly, mutations in some genes leading to Usher syndrome can also manifest as nonsyndromic RP (NSRP) in other individuals, with mutations in Usherin 2A ( USH2A) being a frequent cause of both 17, 18, 19, 20, 21, 22, 23.

This could be due in part to cases in which there is a subtle hearing phenotype, resulting in an incomplete diagnosis of isolated RP. Previously, Usher syndrome was thought to affect approximately 1 in 25,000 individuals, but recent epidemiologic data suggest a higher prevalence 16. These genes are typically involved in ciliary transport or scaffolding proteins important for cellular structure and morphology 5, 10, 11, 12, 13, 14, 15. In addition to this traditional classification, the diagnosis can be refined with genetic testing, as mutations in at least 13 genes are known to cause Usher syndrome 9. Usher syndrome type 3 is the rarest, typically manifesting with progressive hearing loss, early-onset RP, and sporadic vestibular dysfunction 7, 8. Usher syndrome type 2 is characterized by mild, non-progressive hearing loss and early adulthood-onset of RP. Usher syndrome type 1 typically exhibits congenital hearing loss, childhood-onset RP, and possible vestibular dysfunction.

Usher syndrome is categorized clinically into three types (Usher syndrome types 1–3) based predominantly on the onset and progression of hearing loss. The retinal phenotype is characterized by night-blindness, a constricting visual field, and classic pigmentary degeneration seen on imaging 2, 5, 6. It is the most common cause of deaf-blindness and currently irreversible. Usher syndrome is an inherited autosomal recessive condition affecting both hearing and vision, specifically manifesting as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss 1, 2, 3, 4. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Although gene- and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss.

Type 2a usher syndrome