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OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele
  1. R Varga1,2,
  2. M R Avenarius3,
  3. P M Kelley1,
  4. B J Keats4,
  5. C I Berlin5,
  6. L J Hood5,7,
  7. T G Morlet5,8,
  8. S M Brashears9,
  9. A Starr6,
  10. E S Cohn1,
  11. R J H Smith3,
  12. W J Kimberling1
  1. 1Center for Hereditary Communication Disorders, Boys Town National Research Hospital (BTNRH), Omaha, NE, USA
  2. 2National Human Genome Research Institute, NIH, Bethesda, MD, USA
  3. 3Molecular Otolaryngology Research Laboratory, Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
  4. 4Department of Genetics, LSU Health Sciences Center, New Orleans, LA, USA
  5. 5Department of Otorhinolaryngology, LSU Health Sciences Center, New Orleans, LA, USA
  6. 6Department of Neurology, University of California, Irvine, CA, USA
  7. 7Hearing and Speech Sciences Department, Vanderbilt Bill Wilkerson Center, Vanderbilt University Medical Center, Nashville, TN, USA
  8. 8Auditory Physiology and Psychoacoustics Laboratory, A I duPont Hospital for Children, Wilmington, DE, USA
  9. 9Audiology Clinic, A I duPont Hospital for Children, Wilmington, DE, USA
  1. Correspondence to:
 Dr P M Kelley
 BTNRH Genetics Department, 555 North 30th St., Omaha, NE 68131, USA; kelley{at}


Introduction: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene.

Methods: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin.

Results: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype.

Conclusions: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

  • ABR, auditory brainstem responses
  • AD, auditory dys-synchrony
  • AN, auditory neuropathy
  • AR, acoustic reflexes
  • CM, cochlear microphonics
  • DHPLC, denaturing high performance liquid chromatography
  • HL, hearing loss
  • IHC, inner hair cells
  • MDE, mutation detection enhancement
  • MOC, medial olivocochlear
  • NSRAN, non-syndromic recessive auditory neuropathy
  • NSRHL, non-syndromic recessive hearing loss
  • OAE, otoacoustic emissions
  • OHC, outer hair cell
  • SAT, speech awareness threshold
  • SSCP, single strand conformational polymorphism
  • SRT, speech reception threshold
  • OTOF
  • DFNB9
  • otoferlin
  • auditory neuropathy
  • hearing loss
  • temperature sensitive

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  • Published Online First 21 December 2005

  • Competing interests: there are no competing interests