Affiliation:
1. Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre University of Auckland Auckland New Zealand
2. Eye Department, Greenlane Clinical Centre Auckland District Health Board Auckland New Zealand
3. Eye Department – Gisborne Hospital Hauora Tairawhiti Gisborne New Zealand
4. Department of Ophthalmology, Manukau Super Clinic Counties Manukau District Health Board Manukau New Zealand
Abstract
AbstractBackgroundWith the promise of gene replacement therapy, eligible males and females with X‐linked inherited retinal dystrophy (XL‐IRD) should be identified.MethodsRetrospective 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.ResultsFor 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 Māori family showed keratoconus segregating with an ORF15 variant.ConclusionsSignificant 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.