Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome

Abstract

Background: Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum.Here we characterize the clinical phenotypic of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12. Materials and Methods: Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease causing variants in CEP78, CEP250, ARSG, or ABHD12. Results: CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment , retinal pigment epithelium mottling, areas of mid-peripheral hypoautofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypoautofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12 related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and noncongenital SNHL ranging from unreported to severe.Conclusions: This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted.Additionally, genetic screening may be useful in patients that have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Usher syndrome type IV: clinically and molecularly confirmed by novel ARSG variants

“…Comparing the twelve previously described cases supplemented with the presently identified subjects, we observed a fairly similar phenotype (Supplemental Table 3, 4) (Abad-Morales et al 2020 ; Fowler et al 2021 ; Igelman et al 2021 ; Khateb et al 2018 ; Peter et al 2020 ). All individuals were diagnosed with RP with a midlife age of onset (35–60 years), which is later than generally seen in USH type I (first decade) (Tsilou et al 2002 ; Van Camp and Smith 2020 ), type II (first or second decade) (Millan et al 2011 ; Tsilou et al 2002 ), or type III (variable but usually begins in the second decade) (Nisenbaum et al 2021 ) (Fig.…”

“…One individual reported no symptoms of SNHL. However, since no audiometric examination had been performed at his last visit at the age of 48, it could be that he was not yet aware of the possibly increased hearing thresholds or that this will manifest later in life (Igelman et al 2021 ). The reported and calculated age of onset is obviously later than for USH types I and II (congenital), but also later than for type III with an age of onset of SNHL usually in the first decade of life (Fig.…”

“…The classification as a fourth, distinct USH type was confirmed by the identification of three additional variants associated with similar phenotypic characteristics (Peter et al 2020 ). Five other novel ARSG variants were subsequently reported to underlie this newly described phenotype (Fowler et al 2021 ; Igelman et al 2021 ).…”

Inherited causes of combined vision and hearing loss: clinical features and molecular genetics

“…An atypical subtype of USH (USH4) has been associated with disease-causing variants in ARSG (OMIM #618144) [55]; with the genetic spectrum recently expanded to include CEP78 (OMIM #617110), CEP250 (OMIM #609689) and ABHD12 (OMIM #613599) [56]. This form is rare and atypical in that there is a later onset -usually around 40 years of age -of RP and sensorineural hearing loss without vestibular involvement [57].…”

The Phenotypic Spectrum of Patients with PHARC Syndrome Due to Variants in ABHD12: An Ophthalmic Perspective

“…A clinical diagnosis of PHARC was based on the presence of variable combinations of polyneuropathy, HL, ataxia, RP and cataract. Five patients (D-6, F-8, G-9, H-10 and I-11) have been described previously [10,13]. This study was approved by the Medical Ethics Committee of the Erasmus University Medical Center (MEC-2010-359; approval date, 10 October 2013) and by the local review board of the Amsterdam University Medical Centers (approval date, 18 November 2013).…”