Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF)

• Published in: Human mutation Vol. 22; no. 6; pp. 451 - 456
• Main Authors: Rodríguez-Ballesteros, Montserrat, del Castillo, Francisco J., Martín, Yolanda, Moreno-Pelayo, Miguel A., Morera, Constantino, Prieto, Félix, Marco, Jaime, Morant, Antonio, Gallo-Terán, Jaime, Morales-Angulo, Carmelo, Navas, Cristina, Trinidad, Germán, Tapia, M. Cruz, Moreno, Felipe, Castillo, Ignacio del
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-12-2003; Hindawi Limited
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Audiometry, Evoked Response - methods; auditory neuropathy; Child; Child, Preschool; Cochlea - diagnostic imaging; Cochlea - pathology; cochlear implants; DFNB9; Diagnostic Techniques, Otological; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Evoked Potentials, Auditory, Brain Stem - physiology; Female; Genotype; hearing impairment; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - physiopathology; Humans; Infant; Male; Membrane Proteins - genetics; Middle Aged; Mutation; otoacoustic emissions; Otoacoustic Emissions, Spontaneous; OTOF; OTOF gene; Otoferlin; Phenotype; Radiography
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.10274

Inherited hearing impairment affects one in 2,000 newborns. Nonsyndromic prelingual forms are inherited mainly as autosomal recessive traits, for which 16 genes are currently known. Mutations in the genes encoding connexins 26 and 30 account for up to 50% of these cases. However, the individual contribution of the remaining genes to the whole remains undetermined. In addition, for most of the genes there is a need for studies on genotype–phenotype correlations, to identify distinctive clinical features which may direct the molecular diagnosis to specific genes. Here we present a mutation analysis and a genotype–phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). A total of 37 subjects with muta‐tions in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure‐tone audiometry and auditory brainstem responses. Magnetic resonance imaging and computed tomography did not reveal any inner ear malformation. Unexpectedly, transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally in 11 subjects. Altogether, clinical data of these subjects met the diagnostic criteria of auditory neuropathy. A total of 10 subjects had been successfully provided with cochlear implants. The results of our study indicate that genetic diagnosis of subjects with auditory neuropathy and profound hearing impairment should be directed to the otoferlin gene. Our data are of concern to universal screening programs which use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases. Hum Mutat 22:451–456, 2003. © 2003 Wiley‐Liss, Inc.