Molecular Genetics of the Usher Syndrome in Lebanon: Identification of 11 Novel Protein Truncating Mutations by Whole Exome Sequencing

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.

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

“…An unreported variant of ADGRV1 (also known as VLGR1 , MASS1 , KIAA0686 , and GPR98 , MIM# 602851), c.1055C>T [p.(Pro352Leu)], cosegregates with HL in the family PKDF1551 (Figure a). So far, mutations in ADGRV1 have been exclusively associated with Usher syndrome type 2 (USH2C, MIM# 605472) (Besnard et al., ; Reddy et al., ; Weston, Luijendijk, Humphrey, Moller, & Kimberling, ), characterized by congenital mild to severe sensorineural hearing loss, intact vestibular responses, and progressive retinitis pigmentosa. In the family PKDF1551, affected individuals exhibit mild‐to‐severe bilateral sensorineural hearing loss with no vision defects revealed by electroretinogram (Figure b).…”

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations

“…[45][46][47] In addition, cumulative data show that WES can be useful in the discovery of novel causative genes in different medical disciplines, 48 including ophthalmology. 49,50 Next generation sequencing was also reported to be efficient in identifying mutations in known 30,47,51,52 as well as novel 5 USHrelated genes. Moreover, the combination of HM and WES has been proven to be highly efficient in identifying diseasecausative mutations.…”

“…29 It was only recently that the genetic basis of USH in the Arab-Muslim population was studied, and a few sporadic cases were reported. 30,31…”

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

“…Whole-exome library preparation, capturing, sequencing, and bioinformatics analyses were carried out at the McGill University and Genome Quebec Innovation Center, Montreal, Canada as previously described. 18 Whole exome was captured using either SureSelect Human All Exon Kit version 5 (Agilent Technologies) or the Roche Nimblegen SeqCap EZ Human Exome capture kit on 3 mg or 500 ng gnomic DNA, respectively, and sequenced on an Illumina HiSeq 2000 sequencer with paired-end 100-base pair reads. The paired-end sequences were trimmed and aligned to the human reference genome hg19 using BWA (v.0.5.9).…”