Hearing Loss, Hereditary Nonsyndromic - Connexin 26 or 30

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 mutation

Laboratory Testing

  •  Recommended triad
    • GJB2 sequencing
    • GJB6 targeted deletion testing
    • Mitochondrial testing for 2 mutations

Differential Diagnosis

  • Usher syndrome
  • Alport syndrome
  • Pendred syndrome
  • Stickler syndrome
  • Treacher Collins syndrome
  • Waardenburg syndrome
  • Jervell and Lange-Nielsen syndrome
  • Branchiootorenal dysplasia (BOR syndrome)
  • Neurofibromatosis type 2
  • Biotinidase deficiency
  • Mohr-Tranebjaerg syndrome
  • Autoimmune hearing loss

Clinical Background

One in 1,000 infants is born with bilateral, permanent sensorineural hearing loss of at least 40 dB, of which >50% is due to genetic mutations or mitochondrial inheritance. Approximately 70% of the genetically caused hearing loss is nonsyndromic. Mutations in GJB2 and GJB6 cause ~50% of autosomal recessive nonsyndromic hearing loss (NSHL).

Epidemiology

  • Incidence
    • 1/1,000 newborns has profound deafness – 1/2,600 newborns has NSHL
    • 1/6,500 individuals with NSHL has GJB2 mutations
    • 1/30 individuals with NSHL has a GJB6 deletion
      • ~20% of individuals heterozygous for a GJB2 mutation will also have a GJB6 deletion
    • 1/50 individuals with NSHL has a causal mitochondrial mutation
  • Age – birth through early childhood, if caused by GJB2 and GJB6
  • Sex – M:F, equal
  • Ethnicity – 35delG is the most common GJB2 mutation in Caucasians

Inheritance

  • Autosomal recessive (77%) – most GJB2 and GJB6 mutations require two pathogenic mutations in the same gene or a single pathogenic mutation in both genes to cause NSHL
    • In rare cases, may be inherited by autosomal dominant mutations
  • Autosomal dominant (1-2%) – mtDNA mutations with dominant maternal inheritance
  • Mitochondrial – 1555A>G and 7445A>G mutations have variable penetrance and exhibit dominant maternal inheritance
    • Hearing loss in some individuals with the 1555A>G mutation induced by aminoglycosides

Pathophysiology

  • Pathogenic mutations 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 the rapid transport of potassium ions within the cochlear duct required for hearing

Clinical Presentation

  • GJB2 and/or GJB6 mutations usually cause severe prelingual bilateral hearing loss
  • Mitochondrial mutations often cause highly variable sensorineural hearing loss
    • m.7445 A>G mutation – associated with palmar keratoderma and progressive, mild-to-severe hearing loss with childhood onset
    • m.1555A>G mutation – associated with stable, severe-to-profound hearing loss with variable age of onset
  • No other anatomic defects are typically present

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Hearing Loss, Nonsyndromic Panel (GJB2) Sequencing, (GJB6) 2 Deletions and Mitochondrial DNA 2 Mutations 2001992
Method: Polymerase Chain Reaction/Capillary Electrophoresis/Sequencing

Identify the common causes of nonsyndromic hearing loss (NSHL) in GJB2, GJB6, and mitochondrial DNA

Detects only GJB2 sequence variants, two targeted GJB6 deletions, and two targeted mitochondrial mutations

 Sensitivity is ~50% for all cases of NSHL  
Connexin 26 (GJB2), Sequencing 0051374
Method: Nucleic Acid Probe/Fluorescence Signal Amplification/Polymerase Chain Reaction/Sequencing

Identify 95% of GJB2 gene mutations

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

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

Sensitivity is ~45% for all cases of NSHL

GJB6 deletion testing is recommended if only one GJB2 mutation is identified
Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions 2001956
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Identify common GJB6 deletions in individuals with NSHL and a single identifiable GJB2 mutation

Detects only the two targeted GJB6 deletions

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

Identify common mitochondrial mutations

Detects only the two targeted mitochondrial mutations

 2% sensitivity in individuals with NSHL  
Hearing Loss, Nonsyndromic, Connexin 26 (GJB2) 35delG Mutation 0051383
Method: Nucleic Acid Probe/Fluorescence Signal Amplification
 Screening for 35delG/GJB2 mutation common in Caucasians if previously identified in another family member

No other GJB2 gene mutations will be identified

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

75% sensitivity for GJB2 mutations in Caucasians; ~25% sensitivity for all causes of NSHL in Caucasians

ARUP medical director or genetic counselor approval is required prior to testing; before ordering, contact a genetic counselor