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Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations.
Kuruvilla, Shilpa E; Song, Eileen; Raoof, Naz; van Bysterveldt, Katherine; Oliver, Verity F; Hong, Sheng Chiong; Al-Taie, Rasha; Wilson, Graham; Vincent, Andrea L.
Affiliation
  • Kuruvilla SE; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
  • Song E; Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
  • Raoof N; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
  • van Bysterveldt K; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
  • Oliver VF; Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
  • Hong SC; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
  • Al-Taie R; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
  • Wilson G; Eye Department - Gisborne Hospital, Hauora Tairawhiti, Gisborne, New Zealand.
  • Vincent AL; Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
Clin Exp Ophthalmol ; 51(4): 300-312, 2023.
Article in En | MEDLINE | ID: mdl-36882936
ABSTRACT

BACKGROUND:

With the promise of gene replacement therapy, eligible males and females with X-linked inherited retinal dystrophy (XL-IRD) should be identified.

METHODS:

Retrospective observational cohort study to establish the phenotypic and genotypic spectrum of XL-IRD within New Zealand (NZ). Thirty-two probands, including 9 females, with molecularly proven XL-IRD due to RP2 or RPGR mutations, and 72 family members, of which 43 were affected, were identified from the NZ IRD Database. Comprehensive ophthalmic phenotyping, familial cosegregation, genotyping, and bioinformatics were undertaken. Main outcome measures were RP2 and RPGR pathogenic variant spectrum, phenotype in males and females (symptoms, age of onset, visual acuity, refraction, electrophysiology, autofluorescence, retinal appearance), and genotype-phenotype correlation.

RESULTS:

For 32 families, 26 unique pathogenic variants were identified; in RP2 (n = 6, 21.9% of all families), RPGR exons 1-14 (n = 10, 43.75%), and RPGR-ORF15 (n = 10, 34.3%). Three RP2 and 8 RPGR exons 1-14 variants are novel, rare, and cosegregate. Thirty-one percent of carrier females were significantly affected, with 18.5% of families initially classified as autosomal dominant. Of five Polynesian families, 80% had novel disease-causing variants. One Maori family showed keratoconus segregating with an ORF15 variant.

CONCLUSIONS:

Significant disease was present in 31% of genetically proven female carriers, often leading to an erroneous presumption of the inheritance pattern. Pathogenic variants in 44% of the families were in exon 1-14 of RPGR, more frequent than usually described, which may inform the gene testing algorithm. Proving cosegregation in families for novel variants and identifying affected females and males translates to optimised clinical care and potential for gene therapy.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retinitis Pigmentosa / GTP-Binding Proteins / Genetic Diseases, X-Linked / Eye Proteins / Retinal Dystrophies / Membrane Proteins Type of study: Observational_studies / Risk_factors_studies Limits: Female / Humans / Male Country/Region as subject: Oceania Language: En Journal: Clin Exp Ophthalmol Journal subject: OFTALMOLOGIA Year: 2023 Document type: Article Affiliation country: Nueva Zelanda

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retinitis Pigmentosa / GTP-Binding Proteins / Genetic Diseases, X-Linked / Eye Proteins / Retinal Dystrophies / Membrane Proteins Type of study: Observational_studies / Risk_factors_studies Limits: Female / Humans / Male Country/Region as subject: Oceania Language: En Journal: Clin Exp Ophthalmol Journal subject: OFTALMOLOGIA Year: 2023 Document type: Article Affiliation country: Nueva Zelanda