Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations.
Clin Exp Ophthalmol
; 51(4): 300-312, 2023.
Article
em 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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Retinose Pigmentar
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Proteínas de Ligação ao GTP
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Doenças Genéticas Ligadas ao Cromossomo X
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Proteínas do Olho
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Distrofias Retinianas
/
Proteínas de Membrana
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Female
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Humans
/
Male
País/Região como assunto:
Oceania
Idioma:
En
Revista:
Clin Exp Ophthalmol
Assunto da revista:
OFTALMOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Nova Zelândia