title: Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis.
abstract: Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86%) while the presence of both causative alleles characterized 19 patients out 28 (68%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50%), MYO7A (7%), CDH23 (11%), PCDH15 (7%) and USH1G (2%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lenarduzzi
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Vozzi
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rubinato
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Eustacchio
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: T M
authors.initials: TM
authors.lastname: Osland
authors.affiliation: Department of Genetics, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Genetics, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Graziano
authors.affiliation: UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Castorina
authors.affiliation: UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Ambrosetti
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Morgutti
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy. Electronic address: giorgia.girotto@burlo.trieste.it.
authors.forename: G
authors.initials: G
authors.lastname: Girotto
mesh_terms: D000328:Adult; D000483:Alleles; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005817:Genetic Counseling / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D052245:Usher Syndromes / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C442480:CDH23 protein, human; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D016326:Extracellular Matrix Proteins; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D009419:Nerve Tissue Proteins; C477452:USH1G protein, human; C112735:USH2A protein, human; D009218:Myosins