Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF).
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 mutations 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.
Rodríguez-Ballesteros
Montserrat
M
Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
del Castillo
Francisco J
FJ
Martín
Yolanda
Y
Moreno-Pelayo
Miguel A
MA
Morera
Constantino
C
Prieto
Félix
F
Marco
Jaime
J
Morant
Antonio
A
Gallo-Terán
Jaime
J
Morales-Angulo
Carmelo
C
Navas
Cristina
C
Trinidad
Germán
G
Tapia
M Cruz
MC
Moreno
Felipe
F
del Castillo
Ignacio
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001300:Audiometry, Evoked Response / Q000379:methods; D002648:Child; D002675:Child, Preschool; D003051:Cochlea / Q000000981:diagnostic imaging / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D003939:Diagnostic Techniques, Otological; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D017084:Otoacoustic Emissions, Spontaneous; D010641:Phenotype; D011859:Radiography
D008565:Membrane Proteins; C118457:OTOF protein, human; D004247:DNA