Vestibular phenotype‐genotype correlation in a cohort of 90 patients with Usher syndrome

Abstract

Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function. The surprising lack of consistent genotypic to vestibular phenotypic findings as well as no clear vestibular phenotypic patterns among atypical USH cases, indicate that even rigorous vestibular phenotyping data will not reliably differentiate the three USH types.

Usher Syndrome: Genetics of a Human Ciliopathy

“…USH is considered a rare disease, because it has a low prevalence, which ranges from 3 to 6.2 per 100,000 people [1]. Even though a recent report has cast doubts about the vestibular phenotypic differences among the USH subtypes [2], this disease is traditionally classified into three different subtypes depending on the age of onset, severity and progression of the symptoms, and the presence or absence of vestibular dysfunction [3]. USH type 1 (USH1) is the most severe subtype and is characterized by a severe to profound prelingual SNHL, early RP onset and vestibular alterations.…”

Usher Syndrome

“…Exceptions are reported where the most of pathological variants are usually responsible for profound congenital hearing loss with the absence of vestibular function. RP is also severe and rapidly progressive, with early onset [ 56 , 57 ]. Bilateral cochlear implantations (CIs) have provided strong evidence of successful rehabilitation among USH, DFNB2, or DFNA11.…”

Trigenic ADH5/ALDH2/ADGRV1 mutations in myelodysplasia with Usher syndrome

“…USH type III is characterized by progressive postlingual hearing loss, variable onset of RP, and variable vestibular response ( Keats and Corey, 1999 ; Kimberling et al., 2010 ; Mathur and Yang, 2015 ). Vestibular-function phenotype does not, however, map exactly to USH subtype ( Wafa et al., 2021 ). To date, 12 genes have been associated with USH.…”

“…USH type III genes are CLRN1 and HARS1 ( Mathur and Yang, 2015 ). The roles of 3 are disputed; CIB2 , PDZD7 , and HARS are thought to be very rare contributors to USH ( Booth et al., 2018 ; Wafa et al., 2021 ). USH2A is most often identified as mutated in USH type II patients (80%); but ADGRV1 mutation also causes USH type II.…”