Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands

article July/August 2003 䡠 Vol. 5 䡠 No. 4 Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands Arti Pandya, MD1, Kathleen S. Arnos, PhD2, Xia J. Xia, PhD1, Katherine O. Welch, MS2, Susan H. Blanton, PhD3, Thomas B. Friedman, PhD4, Guillermina Garcia Sanchez, MD5, Xiu Z. Liu MD, PhD6, Robert Morell, PhD4, and Walter E. Nance, MD, PhD1 Purpose: Profound hearing loss occurs with a frequency of 1 in 1000 live births, half of which is genetic in etiology. The past decade has witnessed rapid advances in determining the pathogenesis of both syndromic and nonsyndromic deafness. The most significant clinical finding to date has been the discovery that mutations of GJB2 at the DFNB1 locus are the major cause of profound prelingual deafness in many countries.1 More recently, GJB2 mutations have been shown to cause deafness when present with a deletion of the GJB6 gene. We report on the prevalence of GJB2 and GJB6 mutations in a large North American Repository of DNA from deaf probands and document the profound effects of familial ethnicity and parental mating types on the frequency of these mutations in the population. Methods: Deaf probands were ascertained through the Annual Survey of Deaf and Hard of Hearing Children and Youth, conducted at the Research Institute of Gallaudet University. Educational, etiologic, and audiologic information was collected after obtaining informed consent. DNA studies were performed for the GJB2 and GJB6 loci by sequencing and PCR methods. Results: GJB2 mutations accounted for 22.2% of deafness in the overall sample but differed significantly among Asians, African-Americans and Hispanics and for probands from deaf by deaf and deaf by hearing matings, as well as probands from simplex and multiplex sibships of hearing parents. In our sample, the overall incidence of GJB2/GJB6 deafness was 2.57%. Conclusion: GJB2 mutations account for a large proportion of deafness in the US, with certain mutations having a high ethnic predilection. Heterozygotes at the GJB2 locus should be screened for the GJB6 deletion as a cause of deafness. Molecular testing for GJB2 and GJB6 should be offered to all patients with nonsyndromic hearing loss. Genet Med 2003:5(4):295–303. Key Words: GJB2 (connexin 26), GJB6 (connexin 30), genetic hearing loss, national DNA repository, prevalence Approximately 1 in 1000 children is born with a hearing loss severe enough to require special education services and another 1 to 2 in 1000 have a lesser but clinically significant hearing loss. The deafness in at least half of all infants with profound hearing loss can be attributed to genetic factors,2,3 and it is estimated that more than 400 loci may contribute to syndromic and/or nonsyndromic deafness. Nonsyndromic forms account for approximately 67% of genetic deafness, whereas a specific syndrome can be identified in about 33% of cases.2 From the 1Department of Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; 2Department of Biology, Gallaudet University, Washington, DC; 3Department of Human Genetics, University of Virginia Section on Genetics; 4Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland; 5Instituto de la Comunicacion Humana, Lomas de Plateros, Mexico; 6Department of Otolaryngology, University of Miami, Miami, Florida. Arti Pandya, MD, Department of Human Genetics, Medical College of Virginia, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033. Received: February 6, 2003. Accepted: April 30, 2003. DOI: 10.1097/01.GIM.0000078026.01140.68 Genetics IN Medicine Autosomal recessive transmission is found in 77% and autosomal dominant in 22% of genetic deafness. X-linked and mitochondrial forms are much less common in most populations.4 Recently, significant progress has been made in documenting the extreme degree of locus heterogeneity through the mapping and cloning of several dozen genes for syndromic and nonsyndromic deafness. As of 2002, nearly 70 genes for nonsyndromic hearing loss have been localized and the protein product has been identified for approximately onethird of these.5 The pace at which additional genes are discovered is expected to increase in the coming years because of the availability of cochlea-specific cDNA libraries and completion of the sequencing of the human and mouse genomes.6 In addition to confirming locus heterogeneity, molecular studies of hereditary deafness have revealed a more complex pattern of inheritance in some cases. Examples of digenic deafness,7–11 deafness secondary to gene-environment interactions,12,13 or deafness suppressed by specific modifier genes14 have been documented. Future studies are likely to uncover additional examples of oligogenic transmission where the 295 Pandya et al. deafness is attributable to the combined effects of genes at more than one locus and/or specific environmental influences. Perhaps the most remarkable and clinically significant discovery to date has been the finding that mutations involving a single gene, GJB2 (also known as connexin 26), are the most common cause of congenital hereditary deafness in many populations.1,15,16 The GJB2 gene encodes connexin 26, a component of gap junctions. Gap junctions are widely expressed in the cochlea and are thought to participate in the recycling of potassium ions from hair cells to the cochlear endolymph.17 Mutations of GJB2 have been estimated to account for 30% to 40% of all cases of profound, prelingual hereditary deafness in the United States, with a carrier frequency of 2.5% in a Midwestern US population.18 Testing in many other populations has shown that mutations of GJB2 explain 50% to 80% of nonsyndromic recessive deafness16,19 and 10% to 37% of deafness of unknown cause.20,21 One particular mutation, 35delG, accounts for approximately 70% of all recessive mutations of the gene.16 The 167delT mutation has a high prevalence in the Ashkenazi Jewish population,8 with a carrier frequency of approximately 3% to 4%. GJB2 screening has become widely available, in part because the small size of the single coding exon facilitates gene sequencing. PCR-based sequence analysis has been shown to be an efficient method for identifying pathogenic mutations in this gene and is rapidly emerging as the standard of care for the evaluation of newborn infants as well as older children and adults with nonsyndromic deafness of uncertain cause.22,23 Using this and other methods, more widespread use of screening on a clinical basis, particularly in newborns and young children who are identified with hearing loss, will doubtless become more common in the future. Recently, it has been shown that GJB2 mutations, when present with mutations in other nonallelic, functionally related genes, cause deafness. A 342-kb deletion including G (...truncated)