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Alejandro Estrada Cuzcano, Kornelia Neveling, Susanne Kohl, Dror Sharon, Ygal Rotenstreich, Ronald Roepman, Hans Scheffer, Anneke I. Den Hollander, B J. Klevering, Frans P. Cremers; Mutations in C8orf37, Encoding a Ciliary Protein, are Associated with Autosomal Recessive Cone-Rod Dystrophy and Retinitis Pigmentosa with Early Macular Involvement. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1730.
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Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. The purpose of this study was to identify the cause of autosomal recessive (ar) RP and CRD.
Whole-genome homozygosity mapping was conducted in an individual with arRP from a consanguineous family, we identified three sizeable homozygous regions - together encompassing 46 Mb - which were analysed by next-generation sequencing for all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements.
Next-generation sequencing in these three regions revealed a homozygous nonsense mutation (c.497T>A; p.Leu166*) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single nucleotide polymorphism databases or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals with retinal dystrophy which carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice site mutation (c.156-2A>G) in two siblings of a consanguineous family, and homozygous missense mutations (p.Arg177Trp and p.Gln182Arg) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are likely pathogenic. Clinical assessment revealed CRD in four individuals, and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly.
These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies and demonstrate the power of next-generation sequencing combined with homozygosity mapping to identify new disease genes.
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