Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness

Context Mutations in the GJB2 gene are the most common known cause of inher ited 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 G JB2 in the midwestern United States and the prevalence of these mutations i n persons with congenital sensorineural hearing loss ranging in severity fr om moderate to profound, and to derive revised data for counseling purposes . Design Laboratory analysis, performed in 1998, of samples from probands wit h hearing loss for mutations in GJB2 using an allele-specific polymerase ch ain reaction assay, single-strand conformation polymorphism analysis, and d irect sequencing. Setting and Subjects Fifty-two subjects younger than 19 years sequentially referred to a midwestern tertiary referral center for hearing loss or cochl ear implantation, with moderate-to-profound congenital hearing loss of unkn own cause, parental nonconsanguinity, and nonsyndromic deafness with hearin g loss limited to a single generation; 560 control neonates were screened f or 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 hea ring 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 homoz ygotes and compound heterozygotes had deafness. Fourteen of 560 controls we re 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 mutatio ns was determined to be 3.01% (probable range, 2.54%-3.56%). Calculated sen sitivity and specificity for a screening test based on 35delG mutation alon e 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 o f moderate-to-profound congenital inherited deafness in the midwestern Unit ed States. Screening of the GJB2 mutation can be offered to individuals wit h congenital deafness with high sensitivity and specificity by screening on ly for the 35delG mutation,A positive finding should establish an etiologic diagnosis and affect genetic counseling.