Abstract
BackgroundUsher syndrome (USH) is a genetically heterogeneous condition with ten disease-causing genes. The spectrum of genes and mutations causing USH in the Lebanese and Middle Eastern populations has not been described. Consequently, diagnostic approaches designed to screen for previously reported mutations were unlikely to identify the mutations in 11 unrelated families, eight of Lebanese and three of Middle Eastern origins. In addition, six of the ten USH genes consist of more than 20 exons, each, which made mutational analysis by Sanger sequencing of PCR-amplified exons from genomic DNA tedious and costly. The study was aimed at the identification of USH causing genes and mutations in 11 unrelated families with USH type I or II.MethodsWhole exome sequencing followed by expanded familial validation by Sanger sequencing.ResultsWe identified disease-causing mutations in all the analyzed patients in four USH genes, MYO7A, USH2A, GPR98 and CDH23. Eleven of the mutations were novel and protein truncating, including a complex rearrangement in GPR98.ConclusionOur data highlight the genetic diversity of Usher syndrome in the Lebanese population and the time and cost-effectiveness of whole exome sequencing approach for mutation analysis of genetically heterogeneous conditions caused by large genes.
Highlights
Usher syndrome (USH) is a group of recessive inherited disorders characterized by neurosensory deafness and progressive vision loss, with or without vestibular dysfunction [1]
USH1 accounts for 10–35% of all USH cases [3,4] while USH3 is rare and accounts for 2–5% of USH cases in several populations with the exception of the Finnish and Ashkenazi populations where USH3 accounts for 40% of all USH cases [3,4]
We describe the use of whole exome sequencing (WES) to identify Usher causing mutations in 11 unrelated families from Lebanon and the Middle East, of which one was linked to USH1B, three linked to USH2A, and two had weak linkage, with lod score of less than 2, to USH2A in a previous study performed before the identification of the USH1B and USH2A associated genes [28,29]
Summary
Usher syndrome (USH) is a group of recessive inherited disorders characterized by neurosensory deafness and progressive vision loss, with or without vestibular dysfunction [1]. USH1 is the most severe type of the three with profound congenital deafness, vestibular dysfunction and prepubertal progressive retinitis pigmentosa (RP). USH2 is characterized by moderate to severe congenital deafness and post pubertal onset of RP. USH3 is characterized by progressive hearing loss, retinitis pigmentosa and variable vestibular dysfunction. Usher syndrome (USH) is a genetically heterogeneous condition with ten disease-causing genes. The spectrum of genes and mutations causing USH in the Lebanese and Middle Eastern populations has not been described. The study was aimed at the identification of USH causing genes and mutations in 11 unrelated families with USH type I or II
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