Abstract
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.
Highlights
Retinitis pigmentosa is the most common inherited retinal degeneration and a major cause of visual impairment among individuals aged 20–64 years.[1,2] It is genetically heterogeneous and associated with significant variability in age of onset, disease progression and retinal appearance (RetNet; http://www.sph. uth.tmc.edu/retnet/, accessed 31 December 2014).[3]
Retinitis pigmentosa is a disease confined to the eye, some 20–30% of patients have associated non-ocular disease; Usher syndrome, in which retinitis pigmentosa is combined with, typically prelingual, sensorineural hearing loss, is the most frequent syndromic form.[4]
The USH2A gene is located on 1q41 and has two alternatively spliced transcripts: a short one consisting of 21 exons, and a longer one consisting of 51 additional 3′ exons; the latter encodes a 5202 amino-acid matrix protein expressed in photoreceptors and developing cochlear hair cells.[6,7]
Summary
Retinitis pigmentosa is the most common inherited retinal degeneration and a major cause of visual impairment among individuals aged 20–64 years.[1,2] It is genetically heterogeneous (over 60 genes implicated so far) and associated with significant variability in age of onset, disease progression and retinal appearance (RetNet; http://www.sph. uth.tmc.edu/retnet/, accessed 31 December 2014).[3]. Uth.tmc.edu/retnet/, accessed 31 December 2014).[3] retinitis pigmentosa is a disease confined to the eye, some 20–30% of patients have associated non-ocular disease; Usher syndrome, in which retinitis pigmentosa is combined with, typically prelingual, sensorineural hearing loss, is the most frequent syndromic form.[4]. Disease-causing variants in the USH2A gene are the most common cause of Usher syndrome (29% of all cases) and one of the most common causes of nonsyndromic autosomal recessive retinitis pigmentosa (19–23% of all cases).[4,5] The USH2A gene is located on 1q41 and has two alternatively spliced transcripts: a short one consisting of 21 exons, and a longer one consisting of 51 additional 3′ exons; the latter encodes a 5202 amino-acid matrix protein expressed in photoreceptors and developing cochlear hair cells.[6,7] It has been shown that the USH2A protein is required for long-term maintenance of retinal photoreceptors and the development of cochlear cells.[7]
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