Scott et al. (1995) studied a highly inbred Bedouin family with autosomal recessive deafness. The family belonged to a tribe founded approximately 200 years ago by an Arab-Bedouin male who immigrated from Egypt to the southern region of ... Scott et al. (1995) studied a highly inbred Bedouin family with autosomal recessive deafness. The family belonged to a tribe founded approximately 200 years ago by an Arab-Bedouin male who immigrated from Egypt to the southern region of what was then Palestine. He married a local woman and had 7 children, 5 of whom survived to adulthood. Consanguineous marriage had been the rule in the tribe since its third generation. The tribe was then in its seventh generation and consisted of some 3,000 people, all of whom resided in a single geographic area in Israel that is separated from other Bedouin communities. Birth rates within the tribe were high, and polygamy was common. Within the past generation there had been 80 individuals with congenital deafness; all of the affected individuals were descendants of 2 of the 5 adult sons of the founder. The deafness was profound prelingual neurosensory hearing loss with drastically elevated audiometric thresholds at all frequencies. All deaf individuals had an otherwise normal phenotype with the absence of external ear abnormalities, retinopathy, or renal defects, and all were of normal intelligence. Cheng et al. (2005) noted that 4% of 777 unrelated children with hearing loss had medical records that listed an environmental cause for the deafness, and that 11% of those with an unknown etiology were found to have GJB2/GJB6 mutations. Otoacoustic emissions testing to detect functional outer hair cells identified 76 children (10%) with positive emissions, consistent with auditory neuropathy. Five of the patients with auditory neuropathy were homozygous or compound heterozygous for mutations in the GJB2 gene. Cheng et al. (2005) suggested that lack of functional gap junctions due to GJB2 mutations does not necessarily destroy all outer hair cell function. In a survey by Dodson et al. (2011), 127 (54%) of 235 respondents with DFNB1 due to mutations in the GJB2 and/or GJB6 genes reported vestibular dysfunction, compared to 25 (41%) of 61 deaf controls without DFNB1 deafness (p less than 0.03). Most of the DFNB1 patients with vertigo had to lie down for it to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more cases with truncating than nontruncating mutations and was also associated with a family history of dizziness. Dodson et al. (2011) concluded that vestibular dysfunction is more common in DFNB1 deafness than previously recognized. Schimmenti et al. (2008) enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed in a study comparing infants with and without connexin-related hearing loss. Among the 82 infants who underwent newborn screening, 12 infants had passed; 3 had connexin-related hearing loss. There were no differences in newborn hearing screening pass rate, neonatal complication, or hearing loss severity between infants with and without connexin-related hearing loss. Schimmenti et al. (2008) pointed out that not all infants with connexin-related hearing loss will fail newborn hearing screening. Family history correlates significantly with connexin-related hearing loss.
Kelsell et al. (1997) identified a homozygous mutation in the GJB2 gene (121011.0002) in affected members of 3 families with autosomal recessive nonsyndromic sensorineural deafness linked to 13q11-q12 (Brown et al., 1996). By immunohistochemical staining, Kelsell et al. ... Kelsell et al. (1997) identified a homozygous mutation in the GJB2 gene (121011.0002) in affected members of 3 families with autosomal recessive nonsyndromic sensorineural deafness linked to 13q11-q12 (Brown et al., 1996). By immunohistochemical staining, Kelsell et al. (1997) demonstrated that CX26 has a high level of expression in human cochlear cells. Denoyelle et al. (1999) studied 140 children from 104 families with various degrees of sensorineural hearing loss. CX26 mutations were present in 43 (49%) of 88 families with prelingual deafness compared with none of the 16 families with postlingual forms of deafness. CX26-associated deafness varied from mild to profound, and was associated with sloping or flat audiometric curves and a radiologically normal inner ear. Hearing loss was not progressive in 11 of 16 cases tested, and variations in the severity of deafness between sibs were common. Denoyelle et al. (1999) suggested that an important element for genetic counseling is that the severity of hearing loss in DFNB1 is extremely variable and cannot be predicted, even within families. Dahl et al. (2006) identified a homozygous mutation in the GJB2 gene (V37I; 121011.0023) in 4 (8.3%) of 48 Australian children with slight or mild sensorineural hearing loss. All 4 children were of Asian background, and SNP analysis suggested a common founder effect. All 4 children showed bilateral high-frequency sensorineural hearing loss, and 3 also had low-frequency hearing loss. Two additional children who were heterozygous for V37I had mild high-frequency loss maximal at 6kHz, and mild low-frequency loss, respectively. In all, 55 children with slight or mild hearing loss were identified in a screening of 6,240 Australian school children. Tang et al. (2006) analyzed the GJB2 gene in 610 hearing-impaired individuals and 294 controls and identified causative mutations in 10.3% of cases, with equivocal results in 1.8% of cases due to the detection of unclassified, novel, or controversial coding sequence variations or of only a single recessive mutation in GJB2. Thirteen sequence variations were identified in controls, and complex genotypes were observed among Asian controls, 47% of whom carried 2 to 4 sequence variations in the coding region of the GJB2 gene. Iossa et al. (2010) reported an Italian family in which an unaffected mother and 1 of her deaf sons were both heterozygous for an allele carrying 2 GJB2 mutations in cis: the dominant R75Q (121011.0026) and the recessive 35delG (121011.0005), whereas her other deaf son did not carry either of these mutations. The results suggested that the recessive mutation 'canceled out' the effect of the dominant mutation by causing a truncated protein before reaching residue 75. Iossa et al. (2010) suggested that deafness in the 2 sons was due to another genetic cause and highlighted the importance of the report for genetic counseling. - Deafness, Digenic, GJB2/GJB6 Del Castillo et al. (2002) noted that in many patients (10-42%) with autosomal recessive nonsyndromic deafness who were found to have a mutation in the GJB2 gene, the second mutation remained unidentified. They demonstrated that 22 of 33 unrelated such patients, 9 of whom had evidence of linkage to 13q12, were compound heterozygous for a mutation in the GJB2 gene (35delG; 121011.0005) and a deletion in the GJB6 gene (604418.0004). Two subjects were homozygous for the GJB6 mutation. In the Spanish population, the GJB6 deletion was the second most frequent mutation causing prelingual deafness. The authors concluded that mutations in the GJB2 and GJB6 gene can result in a monogenic or digenic pattern of inheritance of prelingual deafness. Del Castillo et al. (2002) reported the deletion as 342 kb, but Del Castillo et al. (2005) stated that more recent sequencing data indicated that the deletion is 309 kb. Pallares-Ruiz et al. (2002) found a deletion in the GJB6 gene in trans in 4 of 6 deafness patients heterozygous for a GJB2 mutation, suggesting a digenic mode of inheritance. In 4 unrelated Spanish patients with autosomal recessive nonsyndromic hearing impairment who were heterozygous for 1 GJB2 mutant allele and did not carry the GJB6 309-kb deletion, del Castillo et al. (2005) identified a GJB6 232-kb deletion, which they referred to as del(GJB6-D13S1854) (see 604418.0006). The deletion was subsequently found in DFNB1 patients in the United Kingdom, Brazil, and northern Italy; haplotype analysis revealed a common founder shared among chromosomes studied from Spain, the United Kingdom, and Italy. In 255 French patients with a phenotype compatible with DFNB1, Feldmann et al. (2004) found that 32% had biallelic GJB2 mutations, and 6% were compound heterozygous for a GJB2 mutation and the GJB6 342-kb deletion. Profoundly deaf children were more likely to have the biallelic GJB2 or heterozygous GJB2/GJB6 mutations. In a study of 777 unrelated children with hearing loss, Cheng et al. (2005) identified GJB2 or GJB6 mutations in 12%; among those with an affected sib, 20% had GJB2 or GJB6 mutations. Ten patients were compound heterozygous for mutations in the GJB2 and GJB6 genes. In 324 probands with hearing loss and 280 controls, including 135 probands and 280 controls previously reported by Tang et al. (2006), Tang et al. (2008) screened for DNA sequence variations in GJB2 and for deletions in GJB6. The 232-kb GJB6 deletion was not found, and the 309-kb GJB6 deletion was found only once, in a patient of unknown ethnicity who was also heterozygous for a truncating mutation in GJB2. Tang et al. (2008) suggested that the 232- and 309-kb deletions in the GJB6 gene may not be common in all populations. - Deafness, Digenic, GJB2/GJB3 Liu et al. (2009) reported digenic inheritance of nonsyndromic deafness caused by mutations in the GJB2 and GJB3 (603324) genes. Three of 108 Chinese probands with autosomal recessive deafness and only 1 mutant GJB2 allele (e.g., 121011.0014) were found to be compound heterozygous with a GJB3 mutation (603324.0011; 603324.0012). The findings were consistent with digenic inheritance; the unaffected parents were heterozygous for 1 of the mutant alleles. - Reviews Willems (2000) reviewed the genetic causes of nonsyndromic sensorineural hearing loss. Petersen and Willems (2006) provided a detailed review of the molecular genetics of nonsyndromic autosomal recessive deafness.
In Tunisia, Ben Arab et al. (1990) estimated the frequency of nonsyndromic autosomal recessive sensorineural deafness to be 7 per 10,000. Chaabani et al. (1995) studied 30 deaf couples in Tunisian and estimated that the number of loci ... In Tunisia, Ben Arab et al. (1990) estimated the frequency of nonsyndromic autosomal recessive sensorineural deafness to be 7 per 10,000. Chaabani et al. (1995) studied 30 deaf couples in Tunisian and estimated that the number of loci for nonsyndromic autosomal recessive deafness in this population was 8.3. Nance et al. (2000) proposed a hypothesis for the high frequency of DFNB1 in many large populations of the world, on the basis of an analysis of the proportion of noncomplementary marriages among the deaf during the 19th century, which suggested that the frequency of DFNB1 may have doubled in the United States during the past 200 years. These so-called noncomplementary marriages between individuals with the same type of recessive deafness are incapable of producing hearing offspring, and the square root of their frequency among deaf marriages provides an upper limit for the prevalence of the most common form of recessive deafness at that time. To explain the increase, they suggested that the combination of intense assortative mating and relaxed selection increased both the gene and the phenotype frequencies for DFNB1. The proposed model assumed that in previous millennia the genetic fitness of individuals with profound congenital deafness was very low and that genes for deafness were then in a mutational equilibrium. The introduction of sign language in Europe in the 17th to 18th centuries was a key event that dramatically improved the social and economic circumstances of the deaf, along with their genetic fitness. In many countries, schools for the deaf were established, contributing to the onset of intense linguistic homogamy, i.e., mate selection based on the ability to communicate in sign language. In some large populations, connexin-26 deafness has been observed but at a much lower frequency. In Mongolia, for example, where there is only 1 residential school for the deaf, sign language was not introduced until 1995. Moreover, the fitness of the deaf is much lower than that of their hearing sibs, assortative mating is much less frequent than in the United States, and connexin mutations account for only 1.3% of all deafness (Pandya et al., 2001). Nance and Kearsey (2004) showed by computer simulation that assortative mating, in fact, can accelerate dramatically the genetic response to relaxed selection. Along with the effects of gene drift and consanguinity, assortative mating also may have played a key role in the joint evolution and accelerated fixation of genes for speech after they first appeared in Homo sapiens 100,000 to 150,000 years ago. In 156 unrelated congenitally deaf Czech patients, Seeman et al. (2004) tested for the presence of mutations in the coding sequence of the GJB2 gene. At least 1 pathogenic mutation was detected in 48.1% of patients. The 3 most common mutations were W24X (121011.0003), 35delG (121011.0005), and 313del14 (121011.0034); the authors stated that testing for only these 3 mutations would detect over 96% of all disease-causing mutations in GJB2 in this population. Testing for 35delG in 503 controls revealed a carrier frequency of 1:29.6 (3.4%) in the Czech Republic. Alvarez et al. (2005) screened the GJB2 gene in 34 Spanish Romani (gypsy) families with autosomal recessive nonsyndromic hearing loss and found mutations in 50%. The predominant allele was W24X (121011.0003), accounting for 79% of DFNB1 alleles. Haplotype analysis suggested that a founder effect is responsible for the high prevalence of this mutation among Spanish gypsies. 35delG (121011.0005) was the second most common allele (17%). Arnos et al. (2008) collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay (1898). Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children increased by a factor of more than 5 in the aforegoing 100 years. Additional analysis within their sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920-1980). Arnos et al. (2008) concluded that their data were consistent with the increase in the frequency of DFNB1 predicted by their previous simulation studies, and provided convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness. Schimmenti et al. (2008) enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed in a study comparing infants with and without connexin-related hearing loss. Overall among these 95 patients, biallelic mutations were identified in 24.7%, but in only 9.1% of infants of Hispanic origin. Schimmenti et al. (2008) concluded that connexin-related hearing loss occurs in one quarter of infants in an ethnically diverse hearing loss population but with a lower prevalence in Hispanic infants. Tekin et al. (2010) screened the GJB2 gene in 534 Mongolian probands with nonsyndromic sensorineural deafness and identified biallelic GJB2 mutations in 23 (4.5%) deaf probands. The most common mutation, IVS1+1G-A (121011.0029), appeared to have diverse origins based on multiple associated haplotypes. Tekin et al. (2010) stated that they found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia compared to western populations, which explained the lower frequency of GJB2 deafness in Mongolia. Barashkov et al. (2011) found homozygosity for the IVS1+1G-A mutation in GJB2 in 70 of 86 patients from the Yakut population isolate in eastern Siberia with nonsyndromic hearing impairment. Six patients were compound heterozygous for this mutation and another pathogenic GJB2 mutation. Audiometric examination was performed on 40 patients who were homozygous for the mutation. Most (85%) had severe to profound hearing impairment, 14% had moderate impairment, and 1% had mild hearing loss. There was some variability in hearing thresholds. The carrier frequency for this mutation in this population was estimated to be 11.7%, the highest among 6 eastern Siberian populations analyzed, and the mutation was estimated to be about 800 years old. The findings were consistent with a founder effect, and Barashkov et al. (2011) postulated a central Asian origin for the mutation. Among 15,799 ethnically diverse individuals screened for DFNB1 carrier status, Lazarin et al. (2013) identified 371 carriers (2.3%), for an estimated carrier frequency of approximately 1 in 43. Five 'carrier couples' were identified. Six individuals were identified as homozygotes or compound heterozygotes. Among 756 individuals of east Asian origin, the carrier frequency was 1 in 22.
Nonsyndromic hearing loss and deafness (DFNB1) is associated with the following:...
DiagnosisClinical DiagnosisNonsyndromic hearing loss and deafness (DFNB1) is associated with the following:Congenital, generally non-progressive sensorineural hearing impairment that is mild to profound by auditory brain stem response testing (ABR) or pure tone audiometry Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 25 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90 dB), or profound (90 dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2000 Hz), or high (>2000 Hz) (see Deafness and Hereditary Hearing Loss Overview).No related systemic findings identified by medical history and physical examinationA family history of nonsyndromic hearing loss consistent with autosomal recessive inheritanceMolecular Genetic TestingGenes. GJB2, which encodes connexin 26, and GJB6, which encodes connexin 30, are the only two genes known to be associated with deafness at the DFNB1 locus:GJB2. Approximately 98% of individuals with DFNB1 have two identifiable GJB2 mutations (i.e., they are homozygotes or compound heterozygotes). More than half of all persons of northern European ancestry with two identifiable GJB2 mutations are homozygous for the c.35delG point mutation [Scott et al 1998]. Data regarding association of the GJB2 allelic variants p.Met34Thr and p.Val37Ile with DFNB1 are discussed in Molecular Genetics.GJB6. Approximately 2% of individuals with DFNB1 have one identifiable GJB2 mutation and one of two large deletions that include a portion of GJB6 (i.e., they are double heterozygotes). A third deletion [del(chr13:19,837,344-19,968,69)8] associated with in-cis reduced expression of both GJB2 and GJB6 mRNA has been recently characterized [Wilch et al 2010]. Clinical testingGJB2 (encoding connexin 26)Sequence analysis. Sequence analysis of the entire coding region detects both mutations in 98% of persons with DFNB1, although mutation screening for DFNB1 is not complete unless screening for the splice site mutation (exon 1 of GJB2) and the large GJB6-containing deletions is included (see Molecular Genetics). Deletion/duplication analysis. Feldmann et al [2009] reported a contiguous gene deletion that included GJB2 and two contiguous connexin genes, GJA3 and GJB6, in addition to a portion of CRYL1 in trans with a known GJB2 deafness-causing mutation in an individual with profound prelingual hearing loss, mental and psychomotor development delay, clinodactyly of the second toes, and a frontal tuft [Feldmann et al 2009]. Targeted mutation analysis. Mutation analysis (looking for only one or several specific mutations) is generally not recommended because this type of analysis has an ethnic bias:The c.35delG mutation is most common in populations of northern European ancestry.The c.167delT mutation is most common in the Ashkenazi Jewish population.The c.235delC mutation is most common in the Japanese and Chinese populations.GJB6 (encoding connexin 30) Targeted mutation analysis. Two large deletions that include a portion of GJB6 (GJB6-D13S1830 and GJB6-D13S1854) are known [Del Castillo et al 2003, del Castillo et al 2005]. GJB6-D13S1830 is the most common GJB6 mutation associated with DFNB1:In one study, 67% of deaf Spanish individuals with one identified GJB2 mutation had this deletion [Wu et al 2002, Stevenson et al 2003].In another study, GJB6-D13S1830 was found in 16% of deaf individuals with one GJB2 mutation [Pandya et al 2003]. Note: Nonsense or missense mutations of GJB6 that would be detected by sequence analysis have not been associated with DFNB1.OtherDeletion analysis. Eleven of 15 members of a large German-American family with recessively inherited, congenital, severe-to-profound nonsyndromic sensorineural hearing loss were found to be homozygous for the GJB2 35delG mutation; however, the remaining four family members carried only a single 35delG mutation. Reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons suggested the presence of an upstream deletion, which was confirmed by array comparative genome hybridization. This deletion - del(chr13:19,837,344-19,968,698) - is 131.4 kb. Its proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6 and it segregates as a completely penetrant DFNB1-causing allele in this family. It was not present in 528 persons with SNHL and monoallelic mutation of GJB2 or GJB6 [Wilch et al 2010]. Characterization of the distant GJB2/GJB6 cis-regulatory regions evidenced by this allele may be required to find the 'missing' DFNB1-causing mutations that are believed to exist.Table 1. Summary of Molecular Genetic Testing Used in DFNB1View in own windowGene SymbolProportion of DFNB1 Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability Two mutationsOne mutationGJB2>99%Sequence analysis 2GJB2 sequence variants98%~2% 3 ClinicalDeletion/ duplication analysis 4Exon(s) or whole-gene deletions <<1% <<1%GJB6<1%Targeted mutation analysisGJB6 deletions 5 NA~2% 3 ClinicalNA = not applicable 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Percentages vary depending on ethnicity. Numbers in table reflect screening of a US population primarily of northern European ancestry.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.5. See Table 3.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.The diagnosis of DFNB1 is established if an individual or affected sibling has recognized deafness-causing mutations in GJB2 or in GJB2 and GJB6.If only one GJB2 mutation is detected and a large deletion that includes a portion of GJB6 is not present, the affected individual is either: (1) deaf and coincidentally a carrier of a GJB2 mutation or (2) deaf with DFNB1 secondary to a novel non-GJB2, non-complementary mutation in the DFNB1 interval. Note: It is difficult to determine the percentage of deaf persons with one GJB2 mutation who fall into these two categories. In a screen of deaf individuals heterozygous for c.35delG, analysis of single-nucleotide polymorphisms (SNPs) in the GJB2-GJB6 region strongly supports the existence of novel mutations in the DFNB1 interval in some of these individuals [Azaiez et al 2004, del Castillo et al 2005]. Testing StrategyTo confirm/establish the diagnosis in a proband. For individuals suspected of having DFNB1:The first step in diagnosis is sequence analysis of GJB2 exon 2 (the coding region of GJB2). If two deafness-causing mutations are identified, the diagnosis of DFNB1 is established.If one deafness-causing mutation is identified, targeted mutation analysis for the two GJB6 deletions, GJB6-D13S1830 and GJB6-D13S1854, is warranted.If no deafness-causing mutations of GJB2 are identified, targeted mutation analysis for GJB6 deletions is not warranted. The frequency of these deletions in all populations is not high enough to result in a large number of deaf individuals homozygous for these mutations. They represent fewer than 0.5% of all individuals with prelingual deafness and without mutations in GJB2 [Del Castillo et al 2003, del Castillo et al 2005, Wilch et al 2010].Carrier testing for at-risk relatives requires prior identification of the deafness-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive condition and are not at risk of developing the condition.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deafness-causing mutations in the family.Genetically Related (Allelic) DisordersOther phenotypes have been associated with mutations in GJB2 and GJB6:GJB2DFNA3 is an autosomal dominant disorder of progressive, moderate-to-severe sensorineural impairmentPalmoplantar keratoderma is characterized by diffuse hyperkeratosis of the hands and feet [Richard et al 1998, Heathcote et al 2000].Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia in which affected individuals have vascularizing keratitis, progressive erythrokeratoderma, and profound sensorineural hearing loss, as well as scarring alopecia and predisposition to squamous cell carcinoma [Richard et al 2002, van Geel et al 2002, van Steensel et al 2002]. KID syndrome is caused by heterozygous mutation in GJB2.Hystrix-like ichthyosis-deafness (HID) syndrome is an autosomal dominant keratinizing disorder characterized by sensorineural hearing loss and hyperkeratosis of the skin. Shortly after birth, erythroderma develops, with spiky and cobblestone-like hyperkeratosis of the entire skin surface appearing by age one year. Severe palmoplantar keratoderma and scarring alopecia occur in some. HID syndrome is considered to differ from KID syndrome in: (1) the extent and time of occurrence of skin symptoms; (2) the severity of keratitis; and (3) electron microscopic features. KID and HID syndromes are caused by the same mutation in GJB2 [van Geel et al 2002].Vohwinkel syndrome is an autosomal dominant condition classified as a "mutilating" diffuse keratoderma because circumferential hyperkeratosis of the digits can lead to autoamputation. Mild-to-moderate sensorineural hearing loss is often associated with the disease [Maestrini et al 1999].Note: The p.Met34Thr mutation described in a family with palmoplantar keratoderma and autosomal dominant sensorineural deafness [Kelsell et al 1997] is not a cause of dominant hearing loss [Cucci et al 2000]. This same DNA variant has been identified in normal hearing persons [Denoyelle et al 1998, Kelley et al 1998], and a screen of 128 grandparents or heads of individual families not known to be related and included in CEPH (Centre d'Etude du Polymorphisme Humain) identified three individuals (2.3%) with the mutation [unpublished data]. The possible pathogenicity of p.Met34Thr remains controversial [Snoeckx et al 2005].With some mutations of GJB2, the epidermal disease and hearing loss cosegregate, while with other mutations, the severity of the disease phenotype varies, suggesting that other factors modify gene expression [Kelsell et al 2001].GJB6Hidrotic ectodermal dysplasia type 2 (Clouston syndrome) is characterized by ectodermal dysplasia, alopecia, and palmoplantar hyperkeratosis. Inheritance is autosomal dominant [Smith et al 2002].
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital (present at birth), non-progressive sensorineural hearing impairment. Intrafamilial variability in the degree of deafness is seen....
Natural HistoryNonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital (present at birth), non-progressive sensorineural hearing impairment. Intrafamilial variability in the degree of deafness is seen.If an affected person has severe-to-profound deafness, an affected sibling with the same GJB2 deafness-causing allelic variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness.If an affected person has mild-to-moderate deafness, an affected sibling with the same GJB2 deafness-causing allelic variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness.A few reports describe children with GJB2 mutations who passed the newborn hearing screen and had somewhat later-onset hearing loss [Norris et al 2006, Orzan & Murgia 2007].In a large cross-sectional analysis of GJB2 genotype and audiometric data from 1531 individuals with autosomal recessive, mild-to-profound, nonsyndromic deafness (median age 8 years; 90% within age 0-26 years) from 16 countries, linear regression analysis of hearing thresholds on age in the entire study and in subsets defined by genotype did not show significant progression of hearing loss in any individual [Snoeckx et al 2005]. This finding is in concordance with prior studies [Denoyelle et al 1999, Orzan et al 1999, Loffler et al 2001]; however, progression of hearing loss cannot be excluded definitively given the cross-sectional nature of the regression analysis. Snoeckx et al [2005] found a slight degree of asymmetry, although the difference in pure tone average at 0.5, 1.0, and 2.0 kHz between ears was less than 15 dB in 90% of individuals.Vestibular function is normal; affected infants and young children do not experience balance problems and learn to sit and walk at age-appropriate times.Except for the hearing impairment, affected individuals are healthy; life span is normal.
Numerous studies have shown that it is possible to predict phenotype based on genotype. The largest study to date involved a cross-sectional analysis of GJB2 genotype and audiometric data from 1531 persons from 16 different countries with autosomal recessive, mild-to-profound, nonsyndromic deafness [Snoeckx et al 2005]. Of the 83 different mutations identified, 47 were classified as non-inactivating (for example, missense mutations) and 36 as inactivating (for example, premature stop codons). By classifying mutations this way, the authors defined three genotype classes:...
Genotype-Phenotype CorrelationsNumerous studies have shown that it is possible to predict phenotype based on genotype. The largest study to date involved a cross-sectional analysis of GJB2 genotype and audiometric data from 1531 persons from 16 different countries with autosomal recessive, mild-to-profound, nonsyndromic deafness [Snoeckx et al 2005]. Of the 83 different mutations identified, 47 were classified as non-inactivating (for example, missense mutations) and 36 as inactivating (for example, premature stop codons). By classifying mutations this way, the authors defined three genotype classes:Biallelic inactivating (I/I) mutations. 1183 of the 1531 persons studied (77.3%) segregated two inactivating mutations that represented 64 different genotypes (36% of all genotypes found). The degree of hearing impairment in this cohort was: profound in 59%-64% of individuals; severe in 25%-28%; moderate in 10%-12%; and mild in 0%-3%.Biallelic non-inactivating (NI/NI) mutations. Ninety-five of the 1531 persons studied (6.2%) segregated two non-inactivating mutations that represented 42 different genotypes (24% of all genotypes found). The degree of hearing impairment was mild in 53% of individuals and severe to profound in 20% of individuals.Compound heterozygous inactivating/non-inactivating (I/NI) mutations. Of the 1531 individuals studied, 253 (16.5%) segregated one inactivating and one non-inactivating mutation that represented 71 different genotypes (40% of all genotypes found). The degree of hearing impairment was profound in 24% to 30% of individuals and severe in 10% to 17% of individuals.Scatter diagrams were constructed to show the binaural mean pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA0.5,1,2kHz) for each person within each genotype class, using individuals homozygous for the c.35delG allele as a reference group:I/I. Only two genotypes differed significantly from the c.35delG homozygote reference group:Individual doubly heterozygous for [GJB2:c.35delG]+[GJB6:del(GJB6-D13S1830)] had significantly greater hearing impairment (median PTA0.5,1,2kHz = 108 dB; p < 0.0001)Individuals who are GJB2 compound heterozygotes for [c.35delG]+[-3179G>A, also known as IVS1+1G→A] had significantly less hearing impairment (median PTA0.5,1,2kHz = 64 dB; p < 0.0001).I/NI. Nine genotypes differed significantly from the c.35delG homozygote reference group:One GJB2 compound heterozygous genotype, [c.35delG]+[p.Arg143Trp], showed significantly greater hearing impairment.Eight genotypes had significantly less hearing impairment. The three genotypes with the least hearing impairment were GJB2 compound heterozygotes [c.35delG]+[p.Val37Ile] (median PTA0.5,1,2kHz = 40 dB, p < 0.0001), [c.35delG]+[p.Met34Thr] (median PTA0.5,1,2kHz = 34 dB, p < 0.0001), and double heterozygotes [GJB6-D13S1830]+[GJB2:p.Met34Thr] (median PTA0.5,1,2kHz = 25 dB, p < 0.0001). The finding in the T/NT genotypic class regarding the threshold distribution in persons with [c.35delG]+[p.Leu90Pro] suggested a bimodal distribution, as seven [c.35delG]+[p.Leu90Pro] GJB2 compound heterozygotes had a PTA0.5,1,2kHz higher than 95 dB and 34 had a PTA0.5,1,2kHz lower than 65 dB, with the PTA0.5,1,2kHz of only one individual falling between these two values (65-95 dB).NI/NI. Three genotypes differed significantly from the c.35delG homozygote reference group in having less hearing impairment: p.Met34Thr homozygotes (median PTA0.5,1,2kHz = 30 dB, p < 0.0001)p.Val37Ile homozygotes (median PTA0.5,1,2kHz = 27 dB, p < 0.0001) [p.Met34Thr]+[p.Val37Ile] compound heterozygotes (median PTA0.5,1,2kHz = 23 dB, p < 0.001)
See Deafness and Hereditary Hearing Loss Overview....
Differential DiagnosisSee Deafness and Hereditary Hearing Loss Overview.Autosomal recessive syndromes with hearing loss and:Retinitis pigmentosa. Three types of Usher syndrome are recognized; all are inherited in an autosomal recessive manner. Usher syndrome type I is characterized by congenital, bilateral, profound sensorineural hearing loss; vestibular areflexia; and adolescent-onset retinitis pigmentosa. Unless fitted with a cochlear implant, individuals with Usher syndrome type 1 do not typically develop speech. Retinitis pigmentosa (RP), a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity. The diagnosis of Usher syndrome type I is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Causative mutations in genes at seven loci (USH1A, MYO7A [USH1B], USH1C [USH1C], CDH23 [USH1D], USH1E, PCDHB15 [USH1F], SANS [USH1G]) have been identified. Usher syndrome type II is characterized by congenital, bilateral sensorineural hearing loss (predominantly in the higher frequencies) ranging from mild to severe and adolescent-to-adult onset of retinitis pigmentosa. Vestibular function is normal. One of the most important clinical distinctions between Usher syndrome type I and Usher syndrome type II is that children with Usher syndrome type I are usually delayed in walking until age 18 months to two years because of vestibular involvement, whereas children with Usher syndrome type II usually begin walking at approximately age one year. Mutations in genes at four different loci cause Usher syndrome type II. Two of these four genes, USH2A (usherin, USH2A) and VLGR1 (USH2C), have been identified. Usher syndrome type III is characterized by postlingual progressive sensorineural hearing loss, late-onset RP, and variable impairment of vestibular function. Mutations in USH3 are causative. Older individuals with Usher syndrome type III may have profound hearing loss and vestibular disturbance resembling Usher syndrome type I.Thyroid enlargement. Pendred syndrome is diagnosed in individuals with: (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia (DVA with cochlear hypoplasia is known as Mondini malformation or dysplasia); and (3) either an abnormal perchlorate discharge test or goiter. Thyroid abnormality is variable; goitrous changes are typically not present at birth but do develop in early puberty (40%) or adulthood (60%). In addition, vestibular function is usually abnormal. Sequence analysis of SLC26A4 identifies disease-causing mutations in about 50% of affected individuals from multiplex families and 20% of individuals from simplex families. Inheritance is autosomal recessive.Cardiac conduction defects. Jervell and Lange-Nielsen syndrome (JLNS) includes congenital profound bilateral sensorineural hearing loss and long QTc, usually greater than 500 msec [Splawski et al 1997]. The latter is associated with tachyarrhythmias, which may culminate in syncope or sudden death. Over half of untreated children with JLNS die prior to age 15 years. Treatment involves use of beta adrenergic blockers, cardiac pacemakers, and implantable defibrillators as well as avoidance of drugs that cause further prolongation of the QT interval and of activities known to precipitate syncopal events. The diagnosis should be considered in any child with congenital sensorineural deafness with negative DFNB1 testing, especially if the child has a history of syncope or seizure or a family history of sudden death before age 40 years. Homozygosity for disease-causing mutations in either KCNQ1 or KCNE1 is confirmatory. Inheritance is autosomal recessive.Autosomal recessive nonsyndromic hearing loss without an identifiable GJB2 mutation and with progression of hearing loss:With a dilated vestibular aqueduct on thin-cut computed tomography (CT) of the temporal bones suggests DFNB4 [Li et al 1998];With a Mondini malformation on thin-cut CT of the temporal bones suggests Pendred syndrome. A perchlorate test and molecular genetic testing of SLC26A4 should be considered [Everett et al 1997].Other causes of congenital severe-to-profound hearing loss should be considered in children who represent single cases in their family: Congenital CMV (cytomegalovirus), the most common cause of congenital, non-hereditary hearing lossPrematurity, low birth weight, low Apgar scores, infection, and any illness requiring care in a neonatal intensive care unit
To establish the extent of involvement in an individual diagnosed with nonsyndromic hearing loss and deafness (DFNB1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of involvement in an individual diagnosed with nonsyndromic hearing loss and deafness (DFNB1), the following evaluations are recommended:Complete assessment of auditory acuity using age-appropriate tests like ABR testing, auditory steady-state response (ASSR) testing, and pure tone audiometryOphthalmologic evaluation for refractive errors Note: It is not possible to exclude retinitis pigmentosa, a manifestation of the three types of Usher syndrome, until near the end of the first decade of life.Treatment of ManifestationsThe following are indicated:Fitting with appropriate hearing aidsEnrollment in an appropriate educational program for the hearing impairedConsideration of cochlear implantation (CI), a promising habilitation option for persons with profound deafnessRecognition that, unlike with many clinical conditions, the management and treatment of severe-to-profound congenital deafness falls largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]SurveillanceThe following are appropriate:Annual examination by a physician familiar with hereditary hearing impairmentRepeat audiometry to confirm stability of hearing lossAgents/Circumstances to AvoidIndividuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important among these for persons with mild-to-moderate hearing loss caused by mutations in GJB2 is avoidance of repeated overexposure to loud noises.Evaluation of Relatives at RiskClarifying the genetic status of a child with a 25% chance of having DFNB1 should be considered shortly after birth so that appropriate early support and management can be provided to the child and family.DNA-based testing can only be considered if both deafness-causing mutations have been identified in an affected family member.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nonsyndromic Hearing Loss and Deafness, DFNB1: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDFNB1GJB213q12.11Gap junction beta-2 proteinThe Connexin-deafness homepage Hereditary Hearing Loss Homepage CCHMC - Human Genetics Mutation DatabaseGJB2DFNB1GJB613q12.11Gap junction beta-6 proteinDeafness Gene Mutation Database The Connexin-deafness homepage Hereditary Hearing Loss Homepage CCHMC - Human Genetics Mutation DatabaseGJB6Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nonsyndromic Hearing Loss and Deafness, DFNB1 (View All in OMIM) View in own window 121011GAP JUNCTION PROTEIN, BETA-2; GJB2 220290DEAFNESS, AUTOSOMAL RECESSIVE 1A; DFNB1A 604418GAP JUNCTION PROTEIN, BETA-6; GJB6GJB2Normal allelic variants. Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from the 5'-untranslated region by an intron of variable size. The coding sequence of GJB2 (exon 2) is 681 base pairs (including the stop codon) and is translated into a 226-amino acid protein.Pathologic allelic variants. See Table 2. Numerous different deafness-causing mutations of GJB2 that result in autosomal recessive nonsyndromic hearing loss are listed on the Connexin-deafness Home page. The most common mutation in individuals of northern European descent is the c.35delG variant. This mutation has also been reported in individuals of Arabic, Bedouin, Indian, and Pakistani ethnicity. Based on tightly linked single-nucleotide polymorphisms (SNPs), a founder mutation arising in southern Europe approximately 10,000 years ago has been predicted [Van Laer et al 2001]. Consistent with this prediction is a northwest-to-southeast c.35delG deafness gradient through the Persian Gulf countries [Najmabadi et al 2005] and a south-to-north c.35delG deafness gradient in Europe [Gasparini et al 2000, Lucotte & Mercier 2001, Rothrock et al 2003].The spectrum of pathologic GJB2 allelic variants diverges substantially among populations as reflected by specific ethnic biases for common mutations. As mentioned above, the c.35delG allele is common among individuals of northern European origin, with a carrier rate of 2% to 4% [Estivill et al 1998, Green et al 1999]; whereas c.235delC is most common in the Japanese population (carrier rate: 1% to 2%) [Abe et al 2000, Kudo et al 2000]; c.167delT is most common in the Ashkenazi Jewish population (carrier rate: 7.5%) [Morell et al 1998]; and p.Val37Ile is most common in Thailand (carrier rate: 11.6%) [Hwa et al 2003]. (For more information, see the Table A.)The p.Met34Thr allelic variant was described first as an autosomal dominant mutation [Kelsell et al 1997], consistent with the study by White et al [1998] in which it was reported to have a dominant-negative effect over wild-type connexin 26 in Xenopus oocytes. This result, however, was later attributed to an artifact in the expression levels of mutant- and wild-type mRNA that were not controlled in the exogenous system [Skerrett et al 2004]. The p.Met34Thr allele has also been considered a pathologic autosomal recessive mutation [Wilcox et al 2000, Houseman et al 2001, Kenneson et al 2002, Wu et al 2002] and a benign allele [Griffith et al 2000, Feldmann et al 2004].Assuming that the p.Met34Thr variant is a benign polymorphism, deaf persons who are compound heterozygotes for [c.35delG]+[p.Met34Thr] would be carriers of only one GJB2 mutation (c.35delG); and their hearing loss must be caused by other unidentified mutations at the DFNB1 locus or by other genes. Because of the large phenotypic variability seen with genetic hearing impairment, a similar degree of variability in hearing loss would be expected in these individuals. However a recent study that included 38 individuals who were compound heterozygotes for [c.35delG]+[p.Met34Thr] showed that all had mild-to-moderate hearing loss with a median PTA0.5,1,2kHz of 34 dB [Snoeckx et al 2005]. The 16 individuals homozygous for p.Met34Thr had an even lower median PTA0.5,1,2khz value (30 dB) [Snoeckx et al 2005].The p.Val37Ile variant has also been reported as nonpathogenic [Kelley et al 1998, Kudo et al 2000, Hwa et al 2003, Wattanasirichaigoon et al 2004]; however, Snoeckx et al [2005] have documented an association of this allelic variant with mild hearing loss in nine of ten genotypic combinations. This result is consistent with other studies of the allele [Abe et al 2000, Wilcox et al 2000, Kenna et al 2001, Lin et al 2001, Marlin et al 2001].Table 2. Selected GJB2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference Sequence c.101T>Cp.Met34Thr 2NM_004004.4 NP_003995.2c.109G>Ap.Val37Ile 2c.35delGp.Gly12Valfs*1c.35G>Tp.Gly12Valg.-3179G>A 3(IVS1+1G>A) -- c.56G>Cp.Ser19Thrc.167delTp.Leu56Argfs*26c.235delCp.Leu79Cysfs*3c.231G>Ap.Trp77Argc.269T>Cp.Leu90Proc.339T>Gp.Ser113Argc.358_360delGAGp.Glu120delc.427C>Tp.Arg143Trpc.487A>Gp.Met163Valc.551G>Cp.Arg184ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. p.Met34Thr and p.Val37Ile are associated with normal-to-mild hearing loss. See discussion in Molecular Genetics, GJB2.3. IVS1+1G>A is -3179 nucleotides from the beginning of exon 2 in the genomic sequence (Reference Sequence NC_000013.9)Normal gene product. Connexin 26 is a beta-2 gap junction protein composed of 226 amino acids. Connexins aggregate in groups of six around a central 2.3-nm pore to form a connexon. Connexons from adjoining cells covalently bond forming a channel between cells. Large aggregations of connexons called plaques are the constituents of gap junctions. Gap junctions permit direct intercellular exchange of ions and molecules through their central aqueous pores. Postulated roles include the rapid propagation of electrical signals and synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in non-excitable tissues.A connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains. Each extracellular domain has three cysteine residues with at least one disulfide bond joining the E1 and E2 loops. The presumed importance of these six cysteines can be inferred from connexin 32 experiments in which any cysteine mutation completely blocks the development of gap-junction conductances between Xenopus oocyte pairs. The third transmembrane domain (M3) is amphipathic and lines the putative wall of the intercellular connexon channel. If the connexons contributed by each cell are composed of the same connexin, the channel is homotypic; if each connexon is formed by a different connexin, it is heterotypic. With the exception of connexin 26, all connexins are phosphoproteins. Connexin 26 forms functional combinations with itself, connexin 32, connexin 46, and connexin 50.Abnormal gene product. Gap junction channels are permeable to ions and small metabolites with relative molecular masses up to approximately 1.2 kd [Harris & Bevans 2001]. Differences in ionic selectivity and gating mechanisms among gap junctions reflect the existence of more than 20 different connexin isoforms in humans. Only a few GJB2 abnormal allelic variants have been tested in recombinant expression systems, with most showing loss of function as a result of altered sorting (p.Gly12Val, p.Ser19Thr, c.35delG, p.Leu90Pro), inability to induce formation of homotypic gap junction channels (p.Val37Ile, p.Trp77Arg, p.Ser113Arg, p.Glu120del, p.Met163Val, p.Arg184Pro and c.235delC), or interference with translation (p.Arg184Pro) [Snoeckx et al 2005].GJB6Normal allelic variants. The majority of gap junction genes have two exons; a few have only one exon; and one, GJB6, has three exons, of which only the third is coding. The translated protein is 261 amino acids long.Pathologic allelic variants. See Table 3. Pathologic allelic variants of GBJ6 are associated with DFNB1, DFNA3, and hidrotic ectodermal dysplasia (Clouston syndrome). The pathologic variants associated with DFNB1 are large deletions (GJB6-D13S1830: ~309 kb; GJB6-D13S1854: ~232 kb) that include much of GJB6 and a large portion of the upstream region. Whether these deletions, which segregate in trans with GJB2 deafness-causing alleles, affect transcription of GJB2 or represent an example of digenic inheritance at the DFNB1 locus has not been determined. (For more information, see Table A.)The GJB6-D13S1830 mutation is most frequent in Spain, France, the United Kingdom, Israel, and Brazil (Portuguese origin), where it accounts for 5.9% to 8.3% of all the DFNB1 alleles. Its frequency is lower in Belgium and Australia (1.3%-1.4%), and it has not been found among deaf Italian GJB2 heterozygotes. In the US, its frequency is 1.6% to 4.0% [Del Castillo et al 2003].The GJB6-D13S1854 mutation accounts for approximately 25% of deaf GJB2 heterozygotes that remained unresolved after screening for GJB6-D13S1830 in Spain; it accounts for 22.2% in the United Kingdom, 6.3% in Brazil, and 1.9% in Northern Italy. This deletion has not been found in deaf GJB2 heterozygotes from France, Belgium, Israel, the Palestinian Authority, the US, or Australia. Haplotype analysis has revealed a common founder for the mutation in Spain, Italy, and the United Kingdom [del Castillo et al 2005].Table 3. Selected GJB6 Pathologic Allelic Variants View in own windowDNA Nucleotide Change 1Protein Amino Acid ChangeReference Sequence GJB6-D13S1830--NM_001110219.1 NP_001103689.1GJB6-D13S1854--del(chr13:19,837,344-19,968,698)--Human genome reference sequence (NCBI Build 36.1 or UCSC version hg18)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Designations are colloquial variants in common use and do not conform to current naming conventions.Normal gene product: Connexin 30 is a beta-6 gap junction protein. It shares an architecture that is common to all connexins (see Molecular Genetics, GJB2).Abnormal gene product: Haploinsufficiency for connexin 30 in carriers of either of the GJB6-including deletions is not associated with a recognized phenotype.
![[increment]](/corehtml/pmc/pmcents/x2206.gif)
GJB6-D13S1830 and