SCiENTiFiC REPORTS | 7: 16783 | DOI:10.1038/s41598-017-16846-9
Combined genetic approaches yield
a 48% diagnostic rate in a large
cohort of French hearing-impaired
, C. Vaché
, C. Blanchet
, M. Willems
, C. Baudoin
, M. Moclyn
, V. Faugère
, B. Isidor
, D. Dupin-Deguine
, M. Nizon
, M. Vincent
, S. Mercier
, C. Calais
, Z. Azher
, L. Lambert
, Y. Perdomo-Trujillo
, F. Giuliano
, M. Claustres
, M. Mondain
& A. F. Roux
Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity,
implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving
the possibilities of oering optimal care to patients. We present the results of a two-year period
of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss.
Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional
approaches including Copy Number Variations, in silico analyses, minigene studies coupled when
appropriate with complete gene sequencing, and a specic assay for STRC. This comprehensive
screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the
other genes (24%). Pathogenic genotypes were identied in 19 dierent genes, with a high prevalence
of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported
in 16% of the genotyped cohort. Four de novo variants were identied. This study highlights the need to
develop several molecular approaches for ecient molecular diagnosis of hearing loss, as this is crucial
for genetic counselling, audiological rehabilitation and the detection of syndromic forms.
Hearing loss (HL) is the most common congenital sensory impairment in humans, and it aects approximately
1 in 600 newborns
. It is estimated that half of the cases have a genetic origin. HL can be non-syndromic (NSHL)
and not associated with other clinical signs, or it can present as one of the symptoms in syndromic forms. In
addition, some non-syndromic forms can evolve to syndromic forms later in life and are then dened as NSHL
. e most common example is Usher syndrome (USH), which alters hearing and in some cases balance
early in life, whereas it is only aer the rst decade that clinical signs of retinitis pigmentosa (RP) will aect the
Over 100 genes have been associated with NSHL and more still with syndromic HL
. Simultaneous screening
of multiple genes is now possible with the advent of massively parallel sequencing (MPS). is approach oers
the possibility of identifying the aetiology of the HL and thus providing proper genetic counselling to the fam-
ilies. Gene testing also impacts the clinical management of patients, as identifying the pathogenic alterations
Laboratoire de Génétique Moléculaire, CHU Montpellier, Montpellier, France.
Service ORL, CHU Montpellier,
Centre National de Référence Maladies Rares “Affections Sensorielles Génétiques”, CHU
Montpellier, Montpellier, France.
Génétique Médicale, CHU Montpellier, Montpellier, France.
Service de Génétique,
CHU-Hôpital Nord, Saint-Etienne, France.
Service de Génétique Médicale, CHU Nantes, Nantes, France.
de Génétique Médicale, CHU Toulouse, Toulouse, France.
Service d’ORL, Otoneurologie et ORL pédiatrique CHU
Toulouse, Toulouse, France.
Service d’ORL, CHU Nantes, Nantes, France.
Laboratoire de Génétique de Maladies
Rares (LGMR) EA7402, Université de Montpellier, Montpellier, France.
Génétique Médicale, Centre de Compétence
des Surdités Génétiques, site constitutif du Centre de Référence des Anomalies du Développement et Syndromes
Malformatifs de l’Est, CHRU Nancy, Nancy, France.
Service de Génétique Médicale, Centre de Référence pour les
Aections Rares en Génétique Ophtalmologique (CARGO), Hôpital Civil, Strasbourg, France.
Service de Génétique
Médicale, CHU Nice, Nice, France. D. Baux and C. Vaché contributed equally to this work. Correspondence and
requests for materials should be addressed to A.R. (email: email@example.com)
Received: 12 September 2017
Accepted: 17 November 2017
Published: xx xx xxxx