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Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

Published:February 26, 2016DOI:https://doi.org/10.1016/j.ophtha.2016.01.021

      Purpose

      USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype–phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP.

      Design

      Clinic-based, longitudinal, multicenter study.

      Participants

      Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium.

      Methods

      Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis.

      Main Outcome Measures

      Low vision and blindness.

      Results

      Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P < 0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P < 0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P < 0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P < 0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations.

      Conclusions

      Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

      Abbreviations and Acronyms:

      APEX (arrayed primer extension), CADD (Combined Annotation Dependent Depletion), RP (retinitis pigmentosa), USH2A (Usher syndrome type 2A), VA (visual acuity), VF (visual field)
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      References

        • Weston M.D.
        • Eudy J.D.
        • Fujita S.
        • et al.
        Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.
        Am J Hum Genet. 2000; 66: 1199-1210
        • van Wijk E.
        • Pennings R.J.
        • te Brinke H.
        • et al.
        Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II.
        Am J Hum Genet. 2004; 74: 738-744
        • McGee T.L.
        • Seyedahmadi B.J.
        • Sweeney M.O.
        • et al.
        Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.
        J Med Genet. 2010; 47: 499-506
        • Tucker B.A.
        • Mullins R.F.
        • Streb L.M.
        • et al.
        Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa.
        Elife. 2013; 2: e00824
        • Vache C.
        • Besnard T.
        • le Berre P.
        • et al.
        Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy.
        Hum Mutat. 2012; 33: 104-108
        • Le Quesne Stabej P.
        • Saihan Z.
        • Rangesh N.
        • et al.
        Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
        J Med Genet. 2012; 49: 27-36
        • Seyedahmadi B.J.
        • Rivolta C.
        • Keene J.A.
        • et al.
        Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa.
        Exp Eye Res. 2004; 79: 167-173
        • Baux D.
        • Larrieu L.
        • Blanchet C.
        • et al.
        Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.
        Hum Mutat. 2007; 28: 781-789
        • Dreyer B.
        • Brox V.
        • Tranebjaerg L.
        • et al.
        Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II.
        Hum Mutat. 2008; 29: 451
        • Lenassi E.
        • Vincent A.
        • Li Z.
        • et al.
        A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.
        Eur J Hum Genet. 2015; 23: 1318-1327
        • Lenassi E.
        • Robson A.G.
        • Luxon L.M.
        • et al.
        Clinical heterogeneity in a family with mutations in USH2A.
        JAMA Ophthalmol. 2015; 133: 352-355
        • Dagnelie G.
        Conversion of planimetric visual field data into solid angles and retinal areas.
        Clin Vision Sciences. 1990; 5: 95-100
        • Neveling K.
        • Collin R.W.
        • Gilissen C.
        • et al.
        Next-generation genetic testing for retinitis pigmentosa.
        Hum Mutat. 2012; 33: 963-972
        • van Huet R.A.
        • Pierrache L.H.
        • Meester-Smoor M.A.
        • et al.
        The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice.
        Mol Vis. 2015; 21: 461-476
        • Kircher M.
        • Witten D.M.
        • Jain P.
        • et al.
        A general framework for estimating the relative pathogenicity of human genetic variants.
        Nat Genet. 2014; 46: 310-315
        • Fishman G.A.
        • Bozbeyoglu S.
        • Massof R.W.
        • Kimberling W.
        Natural course of visual field loss in patients with type 2 Usher syndrome.
        Retina. 2007; 27: 601-608
        • Blanco-Kelly F.
        • Jaijo T.
        • Aller E.
        • et al.
        Clinical aspects of Usher syndrome and the USH2A gene in a cohort of 433 patients.
        JAMA Ophthalmol. 2015; 133: 157-164
        • Sandberg M.A.
        • Rosner B.
        • Weigel-DiFranco C.
        • et al.
        Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.
        Invest Ophthalmol Vis Sci. 2008; 49: 5532-5539
        • Massof R.W.
        First order dynamics of visual field loss in retinitis pigmentosa.
        Clin Vision Sciences. 1990; 5: 1-26
        • Aller E.
        • Larrieu L.
        • Jaijo T.
        • et al.
        The USH2A c.2299delG mutation: dating its common origin in a Southern European population.
        Eur J Hum Genet. 2010; 18: 788-793
        • Baux D.
        • Blanchet C.
        • Hamel C.
        • et al.
        Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.
        Hum Mutat. 2014; 35: 1179-1186
        • Liu X.
        • Bulgakov O.V.
        • Darrow K.N.
        • et al.
        Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells.
        Proc Natl Acad Sci U S A. 2007; 104: 4413-4418
        • Ebermann I.
        • Phillips J.B.
        • Liebau M.C.
        • et al.
        PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome.
        J Clin Invest. 2010; 120: 1812-1823
        • Garcia-Garcia G.
        • Aparisi M.J.
        • Jaijo T.
        • et al.
        Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations.
        Orphanet J Rare Dis. 2011; 6: 65
        • de Castro-Miro M.
        • Pomares E.
        • Lores-Motta L.
        • et al.
        Combined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies.
        PLoS One. 2014; 9: e88410
        • Vona B.
        • Muller T.
        • Nanda I.
        • et al.
        Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations.
        Genet Med. 2014; 16: 945-953
        • Sodi A.
        • Mariottini A.
        • Passerini I.
        • et al.
        MY07A and USH2A gene sequence variants in Italian patients with Usher syndrome.
        Mol Vis. 2014; 20: 1717-1731
        • Bernal S.
        • Meda C.
        • Solans T.
        • et al.
        Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation.
        Clin Genet. 2005; 68: 204-214
        • Aller E.
        • Jaijo T.
        • Beneyto M.
        • et al.
        Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II.
        J Med Genet. 2006; 43: e55
        • Jaijo T.
        • Aller E.
        • Garcia-Garcia G.
        • et al.
        Microarray-based mutation analysis of 183 Spanish families with Usher syndrome.
        Invest Ophthalmol Vis Sci. 2010; 51: 1311-1317
        • Najera C.
        • Beneyto M.
        • Blanca J.
        • et al.
        Mutations in myosin VIIA (MY07A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively.
        Hum Mutat. 2002; 20: 76-77
        • Chen X.
        • Sheng X.
        • Liu X.
        • et al.
        Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.
        PLoS One. 2014; 9: e105439