A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort

• DOI: 10.1097/gim.0b013e3180a03276
• Publication Date: 2007-07-02T08:04:57Z
• Authors: Girish V. Putcha; Bassem A. Bejjani; Stacey Bleoo; Jessica K. Booker; John C. Carey; Nancy Carson; Soma Das; Melissa A. Dempsey; Julie M. Gastier-...; John H. Greinwald; Marcy L. Hoffmann; Linda Jo Bone Jeng; Margaret A. Kenna; Ishrag Khababa; Margaret Lilley; Rong Mao; Kasinathan Murali...; Iris M. Otani; Heidi L. Rehm; Fred Schaefer; William K. Seltzer; Elaine B. Spector; Michelle A. Springer; Karen E. Weck; Richard J. Wenstrup; Stacey Withrow; Bai-Lin Wu; Maimoona A. Zariwala; Iris Schrijver
• Keywords: Male; Canada; Heterozygote; Homozygote; Quantitative Trait Loci; Genetic Diseases, Inborn; Infant, Newborn; Connexins; United States; Connexin 26; 03 medical and health sciences; 0302 clinical medicine; Gene Frequency; Mutation; Connexin 30; Humans; Female; Longitudinal Studies; Hearing Loss

The aim of the study was to determine the actual GJB2 and GJB6 mutation frequencies in North America after several years of generalized testing for autosomal recessive nonsyndromic sensorineural hearing loss to help guide diagnostic testing algorithms, especially in light of molecular diagnostic follow-up to universal newborn hearing screening.Mutation types, frequencies, ethnic distributions, and genotype-phenotype correlations for GJB2 and GJB6 were assessed in a very large North American cohort.GJB2 variants were identified in 1796 (24.3%) of the 7401 individuals examined, with 399 (5.4%) homozygous and 429 (5.8%) compound heterozygous. GJB6 deletion testing was performed in 12.0% (888/7401) of all cases. The >300-kb deletion was identified in only nine individuals (1.0%), all of whom were compound heterozygous for mutations in GJB2 and GJB6. Among a total of 139 GJB2 variants identified, 53 (38.1%) were previously unreported, presumably representing novel pathogenic or benign variants.The frequency and distribution of sequence changes in GJB2 and GJB6 in North America differ from those previously reported, suggesting a considerable role for loci other than GJB2 and GJB6 in the etiology of autosomal recessive nonsyndromic sensorineural hearing loss, with minimal prevalence of the GJB6 deletion.