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Irina Golovleva, Frida Jonsson, Marie Burstedt; Heterogeneity and complexity of EYS mutations in autosomal recessive retinitis pigmentosa in northern Sweden. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3136.
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© ARVO (1962-2015); The Authors (2016-present)
To identify and characterize mutations in EYS gene in order to determine the prevalence of EYS mutations in a cohort of patients affected by autosomal recessive retinitis pigmentosa (ARRP).
To exclude reported genetic ARRP causes allele primer extension (APEX) was performed on 16 genes interrogating 501 sequence variants. Next generation sequencing of 56 ARRP associated genes was used for mutation identification. For detection of copy number variants (CNVs) SNP-array and multiple ligation-dependent probe amplification (MLPA) were applied. Sanger sequencing was performed for mutation screening in all coding exons of EYS gene and for frequency estimation of potentially pathogenic variants in ethnically matched Swedish control individuals. All identified variants were denoted as recommended by Human Genome Variation Society (HGVS). To predict the impact of sequence variants missence mutations and variants detected in intronic sequences were analyzed by bioinformatics tools available via the Alamut software version 2.0.
In a consanguineous family with three affected individuals reported pathogenic variants were excluded in 16 ARRP genes by APEX. However, targeted capture of 56 ARRP genes revealed a heterozygous 8 bp deletion in EYS gene, c.8648_8655del, p.T2904Kfs*4. In a cohort of 122 ARRP cases five patients from five families were homozygous for c.8648_8655del mutation and three cases from two families were compound heterozygous. One stop mutation, c.1155T>A, p.C385* and two novel EYS mutations, c.2992_2992+6delinsTG, p.G998Wfs*5 and c.3877+1G>A were identified. Interestingly, one patient was homozygous for two mutations, c.[1155T>A; 8648_8655del] while his affected sister was compound heterozygous c.[1155T>A; 8648_8655del];[2992_2992+6delinsTG]. Additionally, pair of siblings from another family was carriers of three mutations c.[1155T>A; 8648_8655del];[3877+1G>A]. Finally, duplication of exon 42 was found in three more patients by MLPA.
EYS gene is a common genetic cause of ARRP in northern Sweden with mutations found in more than 10% of cases. At least five bi-allelic mutations, three of which novel, were identified. The second mutation remains to be found in two cases. Considering broad spectrum of EYS mutations a combination of different molecular techniques should be applied when molecular genetic testing is requested.
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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