Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling

Background DFNB1, the locus of an autosomal recessive form of deafness due to mutations in the connexin-26 gene (CX26 or GJB2) is one of the most freq uent hereditary defects in human beings. To date, no clinical characterisat ion of the DFNB1 inner-ear defects has been reported, which precludes the p rovision of prognostic information and genetic counselling. Methods We enrolled, in a prospective study, 140 children from 104 families affected by sensorineural deafness with various degrees of hearing loss. T he children either belonged to a family affected by autosomal recessive dea fness (DFNB family) or represented sporadic cases. We searched for mutation s in the 5' non-coding exon and in the coding region of CX26. Audiometric a nd radiological features were investigated and compared in deaf children wi th and without CX26 mutations. Findings CX26 mutations were present in 43 (49%) of the 88 families with ca ses of prelingual deafness versus none of;the 16 families with postlingual forms of deafness (p < 0 . 01). The inner-ear defects of 54 prelingually de af children with biallelic CX26 mutations were compared with the defects in 57 prelingually deaf children without CX26 mutations. DFNB1 deafness varie d from mild to profound, 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 siblings were common. Interpretation The characteristic audiometric and radiological features of DFNB1 should be the reference used to guide the investigation,by CX26 molec ular diagnostic tests,of deaf children with a compatible phenotype. Prognos tic information can now be given to families: the hearing loss in DFNB1 dea fness is non-progressive in most cases, at least up to young adulthood. An important element for genetic counselling is that the severity of hearing l oss due to DFNB1 is extremely variable and cannot be predicted, even within families.