title: A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.
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.
authors: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.|Eye Hospital, University Medical Centre, Ljubljana, Slovenia.
authors: Eva
authors: E
authors: Lenassi
authors: The Hospital for Sick Children, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.
authors: Ajoy
authors: http://orcid.org/0000-0001-6446-3846
authors: A
authors: Vincent
authors: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.|Ocular Genetics, Singapore Eye Research Institute, Singapore, Singapore.
authors: Zheng
authors: Z
authors: Li
authors: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.
authors: Zubin
authors: Z
authors: Saihan
authors: Wellcome Trust Sanger Institute, Hinxton, UK.
authors: Alison J
authors: AJ
authors: Coffey
authors: UCL Institute of Child Health, London, UK.
authors: Heather B
authors: HB
authors: Steele-Stallard
authors: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.
authors: Anthony T
authors: AT
authors: Moore
authors: Wellcome Trust Sanger Institute, Hinxton, UK.
authors: Karen P
authors: KP
authors: Steel
authors: UCL Ear Institute, London, UK.|National Hospital for Neurology and Neurosurgery, London, UK.
authors: Linda M
authors: LM
authors: Luxon
authors: The Hospital for Sick Children, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.
authors: Elise
authors: E
authors: Héon
authors: UCL Institute of Child Health, London, UK.
authors: Maria
authors: M
authors: Bitner-Glindzicz
authors: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.
authors: Andrew R
authors: AR
authors: Webster
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics; D011795:Surveys and Questionnaires; D052245:Usher Syndromes / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human
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