Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, 
retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A 
retinopathy, we screened USH2A in 186 probands with recessive retinal disease 
and no hearing complaint in childhood (discovery cohort) and in 84 probands with 
recessive retinal disease (replication cohort). Detailed phenotyping, including 
retinal imaging and audiological assessment, was performed in individuals with 
two likely disease-causing USH2A variants. Further genetic testing, including 
screening for a deep-intronic disease-causing variant and large 
deletions/duplications, was performed in those with one likely disease-causing 
change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two 
likely disease-causing variants in USH2A. Some of these variants were 
predominantly associated with nonsyndromic retinal degeneration ('retinal 
disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation 
and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, 
p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, 
p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and 
confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy 
was consistent with retinitis pigmentosa and the audiological phenotype was 
variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal 
degeneration and has a different mutational spectrum to that observed in Usher 
syndrome. The following model is proposed: the presence of at least one 'retinal 
disease-specific' USH2A allele in a patient with USH2A-related disease results 
in the preservation of normal hearing. Careful genotype-phenotype studies such 
as this will become increasingly important, especially now that high-throughput 
sequencing is widely used in the clinical setting.