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Adrian Dockery, Matthew Carrigan, Kirk Stephenson, Niamh Wynne, Giuliana Silvestri, David J Keegan, Paul F Kenna, G. Jane Farrar; A novel mutation in the FLVCR1 gene implicated in Retinitis Pigmentosa without ataxia.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5406.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in FLVCR1 have previously been associated with retinitis pigmentosa (RP) concomitant with posterior column ataxia. Here we describe the identification and evaluation of a rare novel autosomal recessive mutation in FLVCR1 which is implicated solely in RP, with no evidence of posterior column ataxia in a number of affected patients.
The mutation was detected as part of an ongoing target capture NGS study (Target 5000), aimed at identifying candidate variants in pedigrees with inherited retinal degenerations (IRDs). The IRD patient population investigated was obtained via a national network of ophthalmologists in Ireland. If an IRD is suspected in a given pedigree, where consent is provided, DNA samples are taken and sent to a central laboratory for genetic testing. Target 5000 seeks to detect both novel and previously identified pathological mutations in a panel of 254 known retinal degeneration genes, including FLVCR1.
The mutation, FLVCR1 Tyr341Cys, was observed homozygously in seven affected patients across four pedigrees. With the exception of relatives of affected patients, the mutation was only observed once, heterozygously, in our cohort of over 800 sequenced patients, indicating a background allele frequency of <1/1000. All four pedigrees were given the clinical diagnosis of RP prior to genetic testing. No pedigree showed any notable indication of ataxia during clinical evaluation. The age of patients homozygous for the FLVCR1 Tyr341Cys mutation ranged from 26 to 64 years, ages at which symptoms of ataxia should certainly have become apparent. Where samples were available from unaffected relatives, segregation analysis was carried out utilising direct sequencing.
FLVCR1 Tyr341Cys is a very rare mutation, with no previous reports of pathogenicity and no homozygous cases reported in online allele frequency databases. Our sequencing study identified seven homozygotes across multiple pedigrees, all with similar clinical presentations of RP without ataxia, a scenario extremely unlikely to occur by chance for a benign allele, particularly given the low population frequency of Tyr341Cys. We believe this to be the first FLVCR1 mutation conclusively associated with nonsyndromic RP. We hope that this finding will lead to improved genetic diagnosis of IRDs, and that future studies will consider FLVCR1 mutations as potential candidates in cases of RP without ataxia.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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