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Andrea L Vincent, Eileen Song, Shilpa Kuruvilla, Naz Raoof, Katherine van Bysterveldt, Verity F Oliver; Characterising X-linked Inherited Retinal Disease in New Zealand identifies unique population demographics and genotypes.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2770.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize the spectrum of X-linked inherited retinal disease (XL-IRD), and to establish a genotype-phenotype correlation within the New Zealand population.
Probands with XL-IRD (Rod-cone dystrophy RP, Choroideraemia CHM, Congenital stationary night blindness CSNB, Retinoschisis RS, Blue cone monochromatism BCM, and Ocular albinism OA) were identified through family history and positive gene testing, from the 652 patients recruited in the IRD Database. Familial segregation and clinical data for affected male and obligate carrier female was undertaken. Bioinformatics of novel variants included pathogenicity prediction and frequency in population databases.
X-Linked inherited retinal disease was molecularly proven in 39 probands. (XLRP n=16, CHM n=6, CSNB n=5, XLRS n=8, BCM n=2, XLOA n=2), and segregation confirmed in family members where available. 37 unique pathogenic variants were present, with 17 not previously described (43.5%). Mutations in exon ORF15 of RPGR accounted for only 31% (5/16) of XLRP, with one novel change in a NZ Māori family, segregating with disease in 18 family members. One RP2 mutation was identified. Two reportedly unrelated Caucasian families had the same novel mutation (RPGR, intron3, c.248-10A>G). Novel RPGR variants were present in 2 Polynesian/NZ Māori families, the remainder were Caucasian. 4 families showed significant manifestations in female carriers, and were initially diagnosed with dominant disease. For CSNB, disease was attributable to CACNA1F in 4 families, with 75% variants novel. In CHM 83% of variants were novel, and 83% were indels.
In an era where clinical trials for some XL-IRD are underway, a timely diagnosis is necessary. The genotypic spectrum in an XL-IRD New Zealand population differs significantly from that reported in other populations. The majority of variants identified were unique, with 43% of changes not previously reported. The frequency of ORF15 variants in XLRP was 31%, suggesting screening RPGR prior to ORF15 is a more cost effective strategy. Significant disease manifestation in female carriers was observed (33%), consistent with the observation that XLRP may mimic autosomal dominant inheritance. This study highlights the importance of local knowledge in IRD, to optimize diagnosis, targeted gene screening, management, and treatment.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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