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Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.

Crystel Bonnet 1, 2 M'Hamed Grati 1, 2, 3 Sandrine Marlin 1 Jacqueline Levilliers 2 Jean-Pierre Hardelin 2 Marine Parodi 4 Magali Niasme-Grare 4 Diana Zelenika 5 Marc Délépine 5 Delphine Feldmann 4, 1 Laurence Jonard 1, 4 Aziz El-Amraoui 2 Dominique Weil 2 Bruno Delobel 6 Christophe Vincent 7 Hélène Dollfus 8 Marie-Madeleine Eliot 9 Albert David 10 Catherine Calais 11 Jacqueline Vigneron 12 Bettina Montaut-Verient 13 Dominique Bonneau 14 Jacques Dubin 15 Christel Thauvin 16 Alain Duvillard 17 Christine Francannet 18 Thierry Mom 19 Didier Lacombe 20 Françoise Duriez 21 Valérie Drouin-Garraud 22 Marie-Françoise Thuillier-Obstoy 23 Sabine Sigaudy 24 Anne-Marie Frances 25 Patrick Collignon 25 Georges Challe 26 Rémy Couderc 1 Mark Lathrop 5 José-Alain Sahel 27 Jean Weissenbach 28 Christine Petit 2, * Françoise Denoyelle 2, 29, * 
Abstract : BACKGROUND: Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. METHODS: We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). RESULTS: Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. CONCLUSIONS: Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.
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Crystel Bonnet, M'Hamed Grati, Sandrine Marlin, Jacqueline Levilliers, Jean-Pierre Hardelin, et al.. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.. Orphanet Journal of Rare Diseases, 2011, 6 (1), pp.21. ⟨10.1186/1750-1172-6-21⟩. ⟨pasteur-00663885⟩



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