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Konstantinos Nikopoulos, Pietro Farinelli, Beryl Royer-Bertrand, Nicola Bedoni, Ulrika Kjellström, Sten Andreasson, Miltiadis K Tsilimbaris, Chrysanthi Tsika, Stella Blazaki, Carlo Rivolta; Whole exome sequencing reveals CEP78 as a novel disease gene for cone-rod dystrophy. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Cone-rod dystrophy (CRD) is a rare hereditary disorder characterized by cone-driven photoreceptor cell death. To date, mutations in more than 31 genes have been linked to the pathophysiology of CRD, accounting for ~40% of all reported cases. The purpose of this study was to characterize two families (Greek and Swedish) segregating autosomal recessive CRD (arCRD), both at the clinical and the molecular level.
Following detailed clinical evaluation, two affected members from these pedigrees were analyzed by whole exome sequencing (WES). Data processing, including read alignment, variant calling and filtering, was performed using an in-house in silico pipeline. All variants and candidate mutations that survived our filtering procedures were verified by Sanger sequencing.
Affected members of the two families exhibited severe central visual loss with minimal macular changes. Late onset nystagmus was present, while the patients reported severe photophobia. The visual fields (standard automated static perimetry) showed significant reduction of the central sensitivity. The ERG revealed major cone dysfunction and some depression of scotopic recordings. WES in the first proband identified a homozygous single base transition (c.499+1G>T) affecting one of the two invariant nucleotides of the canonical 5’ splice site of intron 4 in CEP78. In addition, the second proband harbored two compound heterozygous mutations resulting in a premature termination codon (Trp212Glyfs*18) and in the alteration of normal splicing of exon 3 (c.499+5G>A), respectively. All changes were absent among the exomes of ~60,000 unrelated control individuals (Exome Aggregation Consortium) strengthening the notion that these changes in CEP78 are bona fide mutations.
This is the first study suggesting that biallelic mutations in CEP78 result in arCRD. According to a number of proteomic studies, CEP78 is a centrosomal protein of unknown function. However, in silico analysis indicates that it is a component of a network including proteins associated with retinal ciliopathies (e.g. CEP290, SDCCAG8, TUBGCP6) implying its possible role in the genesis of the retinal primary cilium. Further molecular assessment and functional studies to uncover the disease mechanisms underlying mutations in this gene are currently ongoing.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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