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 (1) , Magali Niasme-Grare (1) , Diana Zelenika (4) , Marc Délépine (4) , Delphine Feldmann (1, 1) , Laurence Jonard (1, 1) , Aziz El-Amraoui (2) , Dominique Weil (2) , Bruno Delobel (5) , Christophe Vincent (6) , Hélène Dollfus (7) , Marie-Madeleine Eliot (8) , Albert David (1) , Catherine Calais (9) , Jacqueline Vigneron (10) , Bettina Montaut-Verient (11) , Dominique Bonneau (12) , Jacques Dubin (13) , Christel Thauvin (14) , Alain Duvillard (15) , Christine Francannet (16) , Thierry Mom (17) , Didier Lacombe (18) , Françoise Duriez (19) , Valérie Drouin-Garraud (20) , Marie-Françoise Thuillier-Obstoy (21) , Sabine Sigaudy (22) , Anne-Marie Frances (23) , Patrick Collignon (23) , Georges Challe (24) , Rémy Couderc (1) , Mark Lathrop (4) , José-Alain Sahel (25) , Jean Weissenbach (26) , Christine Petit (2) , Françoise Denoyelle (2, 1)

1 CHU Trousseau [APHP]
2 Collège de France - Chaire Génétique et physiologie cellulaire
3 NIDCD
4 CNG - Centre National de Génotypage
5 Centre de Génétique
6 Service ORL
7 Service de génétique médicale
8 Service d'ORL et chirurgie cervico-faciale
9 Service d'oto-rhino-laryngologie (ORL)
10 Maternité Régionale Adolphe Pinard [Nancy]
11 Service ORL
12 Centre de Référence des Maladies Neurogénétiques
13 Service ORL
14 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
15 ORL [CHU de Dijon] - Service Oto-Rhino-Laryngologie [CHU de Dijon]
16 Service de Génétique Médicale [CHU Clermont-Ferrand]
17 Service ORL
18 Service de génétique médicale
19 Service d'ORL
20 Service d'ophtalmologie [Rouen]
21 Service ORL Pédiatrique
22 Département de génétique médicale [Hôpital de la Timone - APHM]
23 Service de Génétique Médicale
24 CHU Pitié-Salpêtrière [AP-HP]
25 Institut de la Vision
26 UMR 8030 - Génomique métabolique

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.

Domaines: Génétique

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⟩