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Genotypic and Phenotypic Correlations in a Large Cohort of Hearing-Impaired Patients

Sandrine Marlin, MD, PhD; Delphine Feldmann, MD, PhD; Hélène Blons, MD, PhD; Natalie Loundon, MD; Isabelle Rouillon, MD; Sébastien Albert, MD; Pierre Chauvin, PhD; Eréa-Noël Garabédian, MD; Rémy Couderc, MD, PhD; Sylvie Odent, MD; Alain Joannard, MD; Sébastien Schmerber, MD; Bruno Delobel, MD; Jacques Leman, MD; Hubert Journel, MD; Hélène Catros, MD; Cédric Lemarechal, MD; Hélène Dollfus, MD, PhD; Marie-Madeleine Eliot, MD; Jean-Louis Delaunoy, MD; Albert David, MD; Catherine Calais, MD; Valérie Drouin-Garraud, MD; Marie-Françoise Obstoy, MD; Cyril Goizet, MD; Françoise Duriez, MD; Florence Fellmann, MD; Jocelyne Hélias, MD; Jacqueline Vigneron, MD; Bettina Montaut, MD; Dominique Matin-Coignard, MD; Laurence Faivre, MD; Clarisse Baumann, MD; Patricia Lewin, MD; Christine Petit, PhD; Françoise Denoyelle, MD, PhD

Arch Otolaryngol Head Neck Surg. 2005;131:481-487.

Objectives  To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1.

Design  Case series.

Setting  Collaborative study in referral centers, institutional practice.

Patients  A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion (GJB6-D13S1830)del.

Main Outcome Measures  The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes.

Results  Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6, (GJB6-D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%).

Conclusion  Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.

Author Affiliations: Unité de Génétique Médicale (Dr Marlin), Service de Biochimie et de Biologie Moléculaire (Drs Feldmann, Blons, and Couderc), and Service d’ORL et de Chirurgie Cervico-faciale (Drs Loundon, Rouillon, Albert, Garabédian, and Denoyelle), INSERM U587, Hôpital d’Enfants Armand-Trousseau, AP-HP, Université Paris VI, Paris; Unité de Recherche en Epidémiologie et Sciences de l’Information, INSERM U707, Faculté de Médecine St-Antoine, Université Paris VI (Dr Chauvin); Unité de Génétique, Hôpital Pontchaillou, Rennes (Dr Odent); Service de Pédiatrie (Dr Joannard) and Service d’ORL (Dr Schmerber), CHU, Grenoble; Centre de Génétique, Hôpital St-Antoine (Dr Delobel) and Centre Rochin (Dr Leman), Lille; Unité de Génétique Médicale, CHR, Vannes (Dr Journel); Centre Gabriel-Deshayes, Auray (Dr Catros); Laboratoire de Génétique Moléculaire et d’Histocompatibilité, CHU, Brest (Dr Lemarechal); Service de Génétique Médicale (Dr Dollfus) and Service d’ORL (Dr Eliot), Hôpital de Hautepierre, and Laboratoire de Diagnostic Génétique, Faculté de Médecine (Dr Delaunoy), Strasbourg; Service de Génétique (Dr David) and Service d’ORL (Dr Calais), Hôtel Dieu, Nantes; Service de Génétique (Dr Drouin-Garraud) and Service d’ORL (Dr Obstoy), Hôpital Charles-Nicolle, Rouen; Unité de Génétique Médicale (Dr Goizet) and Service d’ORL (Dr Duriez), Hôpital Pellegrin, Bordeaux; Service de Cytogénétique, Hôpital St-Jacques, Besançon (Dr Fellmann); Service d’ORL, Hôpital Minjoz, Besançon (Dr Hélias); Maternité Régionale Adolphe-Pinard (Dr Vigneron) and Service d’ORL, Hôpital Central (Dr Montaut), Nancy; Unité de Génétique Médicale, Hôpital, Le Mans (Dr Matin-Coignard); Unité de Génétique Médicale, Hôpital, Dijon (Dr Faivre); Département de Génétique, Hôpital Robert-Debré, Paris (Dr Baumann); Laboratoire Pasteur Cerba, Cergy-Pontoise (Dr Lewin); and Unité de Génétique des Déficits Sensoriels, INSERM U587, Institut Pasteur, Paris (Dr Petit), France.

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