Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

Abstract

We assessed genotype–phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose‐dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue‐specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

Phenotypic and Genetic Characteristics in a Cohort of Patients with Usher Genes

“…This is in keeping with previous reports that show patients with Usher syndrome type 2A develop symptoms at a younger age compared to patients with NS-ARRP associated with USH2A mutations (median age, 15 years vs. 25 years; p < 0.001) [ 3 ]. The mean age of first ocular symptoms in patients with USH associated with USH2A in our cohort is similar to that reported in the literature [ 1 , 3 , 19 , 29 ] and the recent RUSH2A study also found that the age of symptom onset in NS-ARRP patients was 31.8 years compared to 18.4 years in USH2A patients [ 12 ].…”

“…Colombo et al similarly reported worse visual acuities in patients with syndromic USH2A and visual acuity was also worse in patients with more severe USH2A variants [ 30 ]. The RUSH2A trial also reported that their USH2A patients with NS-ARRP had greater preservation of visual fields compared to patients with USH after adjustment of disease duration and age of enrolment [ 12 ].…”

“…In the RUSH2A study, all 42 patients with two truncating variants had a USH2 phenotype and these patients accounted for 53% of their USH2 cohort. They found that the c.2299delG, p.(Glu767SerfsTer21) variant was enriched in patients with USH whilst the c.2276G > T, p.(Cys759Phe) variant was enriched in the NS-ARRP patients and that the overall allele frequency of missense variants was also higher in patients with NS-ARRP [ 12 ]. The authors proposed that there is a dose-related effect on hearing loss and that missense variants occurring within the interfibronectin domain were hypomorphic and were associated with NS-ARRP.…”

“…Genotype-phenotype correlation and confirmation of the pathogenicity of the variants within exon 13 will become increasingly more important as therapeutic interventions are currently being investigated in this exon. The genotype-phenotype correlation in USH2A retinopathy is currently being investigated in the rate of progression in USH2A -related retinal degeneration (RUSH2A) natural history study, which includes 127 internationally recruited patients [ 12 ].…”

“…This led Pierrache et al [ 3 ] to propose that normal cochlear development depends on the presence of at least 1 functional copy of the USH2A protein. More recently, it has been proposed that severe variants that result in a truncated protein might be associated with syndromic disease in patients with USH2A retinopathy that are also associated with earlier disease onset [ 3 , 14 , 15 ], whilst missense variants have been reported to occur in non-syndromic RP [ 12 ]. The RUSH2A natural history study has also found that patients with USH syndrome had more severe visual field loss compared to patients with NS-ARRP secondary to variants in USH2A [ 16 ].…”