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Glenn E. Green, MD; Daryl A. Scott; Joshua M. McDonald; George G. Woodworth, PhD; Val C. Sheffield, MD, PhD; Richard J. H. Smith, MD

JAMA. 1999;281:2211-2216.

Context  Mutations in the GJB2 gene are the most common known cause of inherited congenital severe-to-profound deafness. The carrier frequency of these mutations is not known.

Objectives  To determine the carrier rate of deafness-causing mutations in GJB2 in the midwestern United States and the prevalence of these mutations in persons with congenital sensorineural hearing loss ranging in severity from moderate to profound, and to derive revised data for counseling purposes.

Design  Laboratory analysis, performed in 1998, of samples from probands with hearing loss for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing.

Setting and Subjects  Fifty-two subjects younger than 19 years sequentially referred to a midwestern tertiary referral center for hearing loss or cochlear implantation, with moderate-to-profound congenital hearing loss of unknown cause, parental nonconsanguinity, and nonsyndromic deafness with hearing loss limited to a single generation; 560 control neonates were screened for the 35delG mutation.

Main Outcome Measure  Prevalence of mutations in the GJB2 gene by congenital deafness status.

Results  Of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. The 35delG mutation was identified in 29 of the 41 mutant alleles. Of probands' sibs, all homozygotes and compound heterozygotes had deafness. Fourteen of 560 controls were 35delG heterozygotes, for a carrier rate expressed as a mean (SE) of 2.5% (0.66%). The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01% (probable range, 2.54%-3.56%). Calculated sensitivity and specificity for a screening test based on 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively.

Conclusions  Our data suggest that mutations in GJB2 are the leading cause of moderate-to-profound congenital inherited deafness in the midwestern United States. Screening of the GJB2 mutation can be offered to individuals with congenital deafness with high sensitivity and specificity by screening only for the 35delG mutation. A positive finding should establish an etiologic diagnosis and affect genetic counseling.

Author Affiliations: Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, Head and Neck Surgery (Drs Green and Smith and Mr McDonald), Department of Pediatrics (Mr Scott and Dr Sheffield), and the Howard Hughes Medical Institute (Mr Scott and Dr Sheffield), University of Iowa Hospitals and Clinics, and the Department of Statistics and Actuarial Sciences (Dr Woodworth), University of Iowa, Iowa City. Drs Green, Sheffield, and Smith and Mr Scott contributed equally to this work.

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