One in 500 newborns is born with bilateral, permanent sensorineural hearing loss of at least 40 dB, of which 50% is due to genetic variants or mitochondrial inheritance. Approximately 70% of the genetically caused hearing loss is nonsyndromic.
Diagnosis
Indications for Testing
- Nonsyndromic hearing loss (NSHL) detected during hearing screening tests
- Familial history of NSHL – carrier testing of relatives of individuals with known GJB2, GJB6, or mtDNA variation
Laboratory Testing
- Recommended triad – ~50% sensitivity for all NSHL
- GJB2 sequencing
- GJB6 targeted deletion testing
- Mitochondrial testing for 2 variants
Differential Diagnosis
- Autosomal recessive pattern
- Usher syndrome
- Alport syndrome
- Pendred syndrome
- Jervell and Lange-Nielsen syndrome
- Biotinidase deficiency
- Autosomal dominant pattern
- Waardenburg syndrome
- Neurofibromatosis type 2
- Velocardiofacial syndrome
- Branchiootorenal dysplasia (BOR syndrome)
- Treacher Collins syndrome
- Stickler syndrome
- X-linked pattern
- Mohr-Tranebjaerg syndrome
- Mitochondrial syndromes (eg, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS])
- Autoimmune hearing loss
Background
Epidemiology
- Incidence
- 1/1,000 newborns – profound deafness
- 1/2,600 newborns – nonsyndromic hearing loss (NSHL)
- Homozygous for GJB2 variants – 50%
- Compound heterozygous for GJB2 variant and GJB6 deletion – 2-4%
- Homozygous for GJB6 deletions – rare
- Mitochondrial variants – 1-2%
- 1/2,600 newborns – nonsyndromic hearing loss (NSHL)
- 1/1,000 newborns – profound deafness
- Age – birth through early childhood, if caused by GJB2 and GJB6
- Sex – M:F, equal
- Ethnicity – most common GJB2 variant in Caucasians is 35delG
Inheritance
- GJB2 – autosomal recessive; rarely dominant
- GJB6 – autosomal recessive; resulting from either two GJB6 deletions (rare) or one GJB6 deletion and one GJB2 variant on opposite chromosome
- Mitochondrial DNA – dominant maternal inheritance
- Hearing loss in some individuals with 1555A>G variant is induced by aminoglycosides
Pathophysiology
- Pathogenic variant in GJB1, GJB2, GJB3, or GJB6 genes – known causes of deafness
- GJB2 and GJB6 genes encode connexin 26 and connexin 30, respectively
- Connexins are transmembrane proteins that form vertebrate gap junctions essential to many physiological processes
- Connexins affect rapid transport of potassium ions within cochlear duct required for hearing
Clinical Presentation
- In general, sensorineural hearing loss with no other associated findings
- GJB2 (Connexin 26) or GJB6 (Connexin 30) variants – hearing loss is bilateral and stable with prelingual onset
- Mitochondrial variants often cause sensorineural hearing loss that varies in severity and onset
- m.7445 A>G variant
- Palmar keratoderma
- Progressive
- Mild-to-severe hearing loss with childhood onset
- m.1555A>G variant
- Stable
- Severe-to-profound hearing loss with variable age of onset
- May have predisposition to aminoglycoside ototoxicity
- m.7445 A>G variant
- No other anatomic defects are typically present
ARUP Laboratory Tests
Diagnostic testing or carrier screening for GJB2-related NSHL
May be used as first-tier genetic test for individuals with NSHL
Massively Parallel Sequencing
Diagnostic test for individuals with NSHL and 1 identified GJB2 variant
Carrier screening if family history of GJB6 deletion or for reproductive partner of individual with GJB6 or GJB2 variants
Polymerase Chain Reaction (PCR)/Capillary Electrophoresis
References
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Apps SA, Rankin WA, Kurmis AP. Connexin 26 mutations in autosomal recessive deafness disorders: a review. Int J Audiol. 2007;46(2):75-81.
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Bayazit YA, Yilmaz M. An overview of hereditary hearing loss. ORL J Otorhinolaryngol Relat Spec. 2006;68(2):57-63.
20037285
Matsunaga T. Value of genetic testing in the otological approach for sensorineural hearing loss. Keio J Med. 2009;58(4):216-222.
16650073
Petersen MB, Willems PJ. Non-syndromic, autosomal-recessive deafness. Clin Genet. 2006;69(5):371-392.
12923419
Van Laer L, Cryns K, Smith RJ, et al. Nonsyndromic hearing loss. Ear Hear. 2003;24(4):275-288.
Medical Experts
Mao

Refer to the Hereditary Hearing Loss - GJB2, GJB6, and Gene Panel Testing Test Fact Sheet for more information.