title: Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis.
abstract: Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively.
  
  
  
  In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C.
  
  
  
  Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A.
  
  
  
  We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient's early childhood is of utmost importance, allowing better educational and therapeutic management.
authors.affiliation: Laboratoire de Procédés de criblage moléculaire et cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Tunisie.
authors.forename: Imen
authors.initials: I
authors.lastname: Ben-Rebeh
authors.affiliation: Unité de Génétique et Physiologie de l'Audition, INSERM UMRS 1120, Institut Pasteur, Paris, France.
authors.forename: Mhamed
authors.initials: M
authors.lastname: Grati
authors.affiliation: INSERM UMRS 1120, Institut de la Vision, Paris, France.
authors.forename: Crystel
authors.initials: C
authors.lastname: Bonnet
authors.affiliation: Service d'Ophtalmologie, C.H.U. H. Bourguiba de Sfax, Tunisie.
authors.forename: Walid
authors.initials: W
authors.lastname: Bouassida
authors.affiliation: Laboratoire de Procédés de criblage moléculaire et cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Tunisie.
authors.forename: Imen
authors.initials: I
authors.lastname: Hadjamor
authors.affiliation: Laboratoire de Procédés de criblage moléculaire et cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Tunisie.
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.affiliation: Service d'O.R.L., C.H.U.H. Bourguiba de Sfax, Tunisie.
authors.forename: Abdelmonem
authors.initials: A
authors.lastname: Ghorbel
authors.affiliation: Unité de Génétique et Physiologie de l'Audition, INSERM UMRS 1120, Institut Pasteur, Paris, France; INSERM UMRS 1120, Institut de la Vision, Paris, France; Collège de France, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.affiliation: Laboratoire de Procédés de criblage moléculaire et cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Tunisie.
authors.forename: Saber
authors.initials: S
authors.lastname: Masmoudi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014416:Tunisia; D052245:Usher Syndromes / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; C118970:USH1C protein, human; D009218:Myosins