Hearing Loss, Hereditary Nonsyndromic - Connexin 26 or 30

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
  • Background
  • Lab Tests
  • References
  • Related Topics

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

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%
  • 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 2 GJB6 deletions (rare) or 1 GJB6 deletion and 1 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
  • No other anatomic defects are typically present
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Hearing Loss, Nonsyndromic Panel (GJB2) Sequencing, (GJB6) 2 Deletions and Mitochondrial DNA 2 Mutations 2001992
Method: Polymerase Chain Reaction/Capillary Electrophoresis/Sequencing

Limitations 

Diagnostic errors can occur due to rare sequence variations

GJB2 regulatory region variants, deep intronic variants, and large deletions or duplications will not be detected

GJB6 and mitochondrial DNA variants, aside from those targeted, will not be detected

Etiology of hearing loss due to other genetic or environmental causes will not be determined

Connexin 26 (GJB2), Sequencing 0051374
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Diagnostic errors can occur due to rare sequence variations

Large GJB2 gene deletions or deep intronic variants will not be identified

Hearing loss caused by other genetic or environmental causes will not be detected

Expanded Hearing Loss Panel, Sequencing (56 Genes) and Deletion/Duplication (53 Genes) 2008803
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

Negative result does not exclude diagnosis of hereditary hearing loss

Not detected – regulatory region variants, deep intronic variants, variants in genes not targeted, large deletions or duplications in ESPNOTOA, and STRC genes, or in exon 5 of DNMT1 gene or exon 18 of DIAPH1 gene

Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions 2001956
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Limitations 

GJB6 variants other than 2 targeted will not be identified

Etiology of hearing loss due to other genetic or environmental causes will not be determined

Diagnostic errors can occur due to rare sequence variations

Hearing Loss, Nonsyndromic, Mitochondrial DNA 2 Mutations 2002044
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Diagnostic errors can occur due to rare sequence variations

Variants other than 2 targeted will not be identified

Etiology of hearing loss due to other genetic or environmental causes will not be determined

General References

Apps SA, Rankin WA, Kurmis AP. Connexin 26 mutations in autosomal recessive deafness disorders: a review. Int J Audiol. 2007; 46(2): 75-81. PubMed

Bayazit YA, Yilmaz M. An overview of hereditary hearing loss. ORL J Otorhinolaryngol Relat Spec. 2006; 68(2): 57-63. PubMed

Matsunaga T. Value of genetic testing in the otological approach for sensorineural hearing loss. Keio J Med. 2009; 58(4): 216-22. PubMed

Petersen MB, Willems PJ. Non-syndromic, autosomal-recessive deafness. Clin Genet. 2006; 69(5): 371-92. PubMed

Van Laer L, Cryns K, Smith RJ, Van Camp G. Nonsyndromic hearing loss. Ear Hear. 2003; 24(4): 275-88. PubMed

Medical Reviewers

Last Update: October 2017