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.

Keywords: Usher syndrome; atypical Usher syndrome; balance; novel variants; vestibular.

FIGURE 1

Total vestibulo‐ocular reflex response to caloric stimulation in degrees per second for all patients with pathologic variants in Usher genes. All symbols falling below the dotted line represent individuals with a bilateral caloric weakness [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Gain of the vestibulo‐ocular reflex (VOR) induced during rotary chair testing for individual patients grouped by genetically defined type of Usher syndrome [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Sensory organization test (SOT) equilibrium scores for all six conditions (averaged over three trials) and composite score for all patients. Filled symbols represent scores that fall within the normal range by age, unfilled symbols are scores below the fifth percentile for age. Composite scores that fall within the shaded gray area indicate patients are considered at risk for falls [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Pedigree of family LMG353 segregating atypical Usher syndrome. Squares and circles represent male and female patients. Four different variants of MYO7A are cosegregating with the phenotype in four patients (ID: 1999‐2002) with atypical Usher syndrome. Genotypes are mentioned under each patient