GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss

Clinical characteristics: GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is the most common genetic cause of congenital (present at birth) severe-to-profound non-progressive sensorineural hearing loss in many world populations. In countries where available, newborn hearing screening (NBHS) typically identifies severe-to-profound hearing loss.

GJB2-AR NSHL can also be mild to moderate and is usually not progressive; however, it can progress. Congenital mild-to-moderate GJB2-AR NSHL is not detected by NBHS.

GJB2-AR NSHL has no related systemic findings.

Diagnosis/testing: The diagnosis of GJB2-AR NSHL is established in a proband with suggestive findings and biallelic GJB2 pathogenic variants identified by molecular genetic testing. Of note: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.

Management: Treatment of manifestations: It is recommended that NBHS be completed by age one month, the genetic diagnosis be established by age three months, and early intervention begun by age six months. (This recommendation is also known as "the 1-3-6 benchmark.") In the United States, the states that recommend the 1-3-6 benchmark should actually strive for a "1-2-3" timeline.

Because children with severe-to-profound hearing loss who are candidates for cochlear implantation can attain levels of social functioning and education indistinguishable from those of normal-hearing peers, cochlear implantation should be performed as soon as possible.

Children with mild-to-moderate hearing loss can be treated with hearing aids customized to the child's age and severity of hearing loss.

Surveillance: Most children with severe-to-profound GJB2-AR NSHL who are cochlear implant recipients initially require frequent follow-up visits with their cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist) for assessment of speech recognition and equipment check. Once the cochlear implant recipient and their family become comfortable with the cochlear implant, many of these tasks can be performed by the family at home.

All children with mild-to-moderate GJB2-AR NSHL require follow-up audiograms annually to detect any progression of hearing loss. Children using hearing aids typically have an annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist to examine the ears, obtain an audiogram, and check hearing aid function.

Agents/circumstances to avoid: Individuals with mild-to-moderate hearing loss should avoid environmental exposures known to cause hearing loss. Most important for persons with GJB2-related mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises (i.e., >75 decibels), particularly secondary to earbud use. Note that the headphone safety feature built into many smartphones can be set to a maximum limit of decibels.

Evaluation of relatives at risk: With limited exceptions, it is appropriate to clarify the genetic status of sibs of a proband with GJB2-AR NSHL; early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.

Genetic counseling: GJB2-AR NSHL is inherited in an autosomal recessive manner. The parents of a child with GJB2-AR NSHL are typically heterozygous for a GJB2 pathogenic variant. In populations with a high carrier rate, it is possible that either one or both parents of a child with GJB2-AR NSHL also have GJB2-AR NSHL. If both parents are known to be heterozygous for a pathogenic variant, each sib of an individual with GJB2-AR NSHL has at conception a 25% chance of inheriting biallelic pathogenic variants and having hearing loss, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial GJB2 pathogenic variants. Once the GJB2 pathogenic variants have been identified in a family member with GJB2-AR NSHL, prenatal and preimplantation genetic testing for GJB2-AR NSHL are possible.