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Kinga Bujakowska, Emily Place, Mark Consugar, Daniel Taub, Aliete Langsdorf, Carol Weigel-DiFranco, Shyana Harper, Xiaowu Gai, Eliot Berson, Eric Pierce; Comprehensive genetic analysis of an Usher I patient cohort. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1581.
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© ARVO (1962-2015); The Authors (2016-present)
Usher syndrome is the most frequently inherited dual impairment of vision and hearing. Usher syndrome type 1 (USH1) is the most severe form characterized by profound congenital deafness, vestibular dysfunction and prepubescent onset of retinal degeneration. Currently, there are six genes associated with USH1: Myosin VIIa (MYO7A), Harmonin (USH1C), Cadherin-23 (CDH23), Protocadherin-15 (PCDH15), Sans (USH1G) and recently identified CIB2. The products of five of these genes have recently been identified to be part of the calyceal processes of photoreceptors. The purpose of the study was to genetically characterize a cohort of 49 USH1 probands.
An USH1 cohort of 49 probands, partially pre-screened for MYO7A mutations, was high-throughput sequenced for targeted exons of genes associated with inherited retinal degenerations. Genetically unsolved samples were subsequently screened for deletions using a custom design comparative genomic hybridization (CGH) array. When possible, the likely pathogenic variants were confirmed by co-segregation in available family members with Sanger sequencing.
Selective exon capture and Illumina sequencing provided excellent coverage of the targeted exons, with >95% of exons having >10X sequence depth. With this sequencing approach, we were able to solve 35% of 49 cases, where mutations in MYO7A were the most frequent (16%), followed by CDH23 (10%) and USH1C (6%). 37% of the samples contained one heterozygous likely pathogenic change in a USH1 gene. The remaining, 28% did not carry mutations in any known USH1 gene. CGH array analyses for unsolved cases is in progress and will be reported.
Targeted exon sequencing provides an effective approach for genetic diagnostic testing of patients with Usher syndrome. The results of this study show that there is a considerable number of USH1 patients with an unknown genetic cause of the disease, indicating additional genetic loci for this condition. Acknowledgements: This work was supported by grants from the National Eye Institute (EY012910) and the Foundation Fighting Blindness.
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