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

Crystel Bonnet; M'Hamed Grati; Sandrine Marlin; Jacqueline Levilliers; Jean-Pierre Hardelin; Marine Parodi; Magali Niasme-Grare; Diana Zelenika; Marc Délépine; Delphine Feldmann; Laurence Jonard; Aziz El-Amraoui; Dominique Weil; Bruno Delobel; Christophe Vincent; Hélène Dollfus; Marie-Madeleine Eliot; Albert David; Catherine Calais; Jacqueline Vigneron; Bettina Montaut-Verient; Dominique Bonneau; Jacques Dubin; Christel Thauvin; Alain Duvillard; Christine Francannet; Thierry Mom; Didier Lacombe; Françoise Duriez; Valérie Drouin-Garraud; Marie-Françoise Thuillier-Obstoy; Sabine Sigaudy; Anne-Marie Frances; Patrick Collignon; Georges Challe; Rémy Couderc; Mark Lathrop; José-Alain Sahel; Jean Weissenbach; Christine Petit; Françoise Denoyelle

doi:10.1186/1750-1172-6-21

Journal articles

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, *}

* Corresponding author

1 Service de génétique et embryologie médicales [CHU Trousseau]

2 Chaire Génétique et physiologie cellulaire

CdF (institution) - Collège de France

3 NIDCD

4 Service de Biochimie et de Biologie Moléculaire [CHU Trousseau]

5 CNG - Centre National de Génotypage

6 Centre de Génétique

7 Service ORL

8 Service de génétique médicale

9 Service d'ORL et chirurgie cervico-faciale

10 Service d'ORL et de Chirurgie Cervicofaciale

11 Service d'oto-rhino-laryngologie (ORL)

12 Maternité Régionale Adolphe Pinard [Nancy]

13 Service ORL

14 Centre de Référence des Maladies Neurogénétiques

15 Service ORL

16 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)

17 ORL [CHU de Dijon] - Service Oto-Rhino-Laryngologie [CHU de Dijon]

18 Service de Génétique Médicale [CHU Clermont-Ferrand]

19 Service ORL

20 Service de génétique médicale

21 Service d'ORL

22 Service d'ophtalmologie [Rouen]

23 Service ORL Pédiatrique

24 Département de génétique médicale [Hôpital de la Timone - APHM]

25 Service de Génétique Médicale

26 CHU Pitié-Salpêtrière [AP-HP]

27 Institut de la Vision

28 UMR 8030 - Génomique métabolique

29 Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau]

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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Journal articles

Domain :

Life Sciences [q-bio] / Genetics

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

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