Exploring the clinical and epidemiological complexity of GJB2‐linked deafness

Abstract

GJB2 mutation analysis was performed in 179 unrelated subjects with sporadic or familial hearing loss (HL). Among 57 families, 18 showed a vertical transmission of HL, the disease being present in two or three generations. Besides 155 nonsyndromic cases, 24 patients presenting with extra-auditory clinical signs were included in the molecular study. GJB2 mutation analysis was also performed in 19 subjects with an anamnestic history of perinatal risks factors for acquired HL. The 35delG mutation accounted for 22.1% of analyzed chromosomes in sporadic cases and 39.4% in familial cases; 35delG prevalence reached 41% in autosomal recessive and 44.4% in pseudodominant pedigrees. Two novel GJB2 mutations were identified in compound heterozygosity with 35delG allele (D159V, 284ins/dup[CACGT]). Two 35delG homozygous subjects were identified among HL cases classified as environmental in origin. Four patients 35delG heterozygous (35delG/V95M, 35delG/L90P, 35delG/167delT, and 35delG/?) and two homozygous presented with extra-auditory clinical signs involving different organs (skin, vascular system, hemopoietic lineages, and thyroid). In a high proportion of 35delG heterozygous HL patients (52%), no second GJB2 mutation was detected. The reported data highlight the complexity of the genetic epidemiology of GJB2-linked deafness, further enlarging the spectrum of situations in which GJB2 mutation analysis should be performed. The presence of extra-auditory signs in a significant portion of GJB2-mutated patients suggests the possibility that GJB2 loss of function could contribute to clinical phenotypes presenting in association with deafness. This hypothesis deserves further investigation. The failure to identify a presumed partnering GJB2 mutation in a high proportion of deaf patients remains a challenging problem to be clarified.

Progress in Understanding GJB2-Linked Deafness

“…The hearing impairment associated with GJB2 mutations is frequently severe or profound, but there can be considerable variations among individuals carrying the same mutation, even belonging to the same family [14, 23, 24, 25]. Several observations have reported that mutations in the GJB2 gene may be found in cases with disease of mild or moderate severity [25, 26, 27].…”

“…Deafness is usually stable, but progression has been reported [23, 26, 28]. Similarly, the hearing deficit is commonly symmetric but asymmetry in the degree of hearing loss between ears has been noticed [25, 29]. Onset is nearly always prelingual, but not necessarily congenital [30].…”

“…Several observations have reported that mutations in the GJB2 gene may be found in cases with disease of mild or moderate severity [25, 26, 27]. Deafness is usually stable, but progression has been reported [23, 26, 28].…”

“…A common observation in all the reported studies investigating the prevalence of GJB2 mutations in the deaf population, is the high frequency of deaf subjects carrying only one mutated allele [25, 28, 47]. The relatively high number of hearing-impaired individuals with 35delG mutation detectable on only one allele seems not to be justified by the occurrence of mutations not routinely addressed by molecular analysis (such as mutations in the 5′ and 3′ noncoding sequences or in the promoter region of GJB2 gene and splicing mutations) or by coincidental heterozygosity due to high 35delG frequency in the normal population.…”

Review Studies of GJB2 Gene in Patients with Hearing Impairment in Pakistan

“…Heterozygous W44C mutation is present in the extracellular loop E1 (allows the interactions between adjacent cells connexons) of the protein. Other known GJB2 mutations are E47X, I20T, R184P, L90P, delE120 and V95M [81].…”