title: Molecular genetics of the Usher syndrome in Lebanon: identification of 11 novel protein truncating mutations by whole exome sequencing.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  Whole exome sequencing followed by expanded familial validation by Sanger sequencing.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Departments of Human Genetics and Obstetrics-Gynecology, McGill University Health Centre, Montreal, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Reddy
authors.affiliation: McGill University and Genome Quebec Innovation Centre and Department of Human Genetics, Montreal, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Otorhinolaryngology, Hôpital Sacré-Coeur, Baabda, Lebanon.
authors.forename: Elie
authors.initials: E
authors.lastname: El Zir
authors.affiliation: Department of Ophthalmology, American University of Beirut, Beirut, Lebanon.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mansour
authors.affiliation: Unité de génétique médicale, Faculté de médecine, Université Saint Joseph, Beirut, Lebanon.
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.affiliation: McGill University and Genome Quebec Innovation Centre and Department of Human Genetics, Montreal, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Departments of Human Genetics and Obstetrics-Gynecology, McGill University Health Centre, Montreal, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
mesh_terms: D000595:Amino Acid Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome; D016326:Extracellular Matrix Proteins / Q000235:genetics; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D007861:Lebanon; D008969:Molecular Sequence Data; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D017423:Sequence Analysis, RNA; D052245:Usher Syndromes / Q000235:genetics* / Q000378:metabolism
chemical_list: C417525:ADGRV1 protein, human; C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D043562:Receptors, G-Protein-Coupled; C112735:USH2A protein, human; D009218:Myosins