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 – ~50% sensitivity for all NSHL
    • 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 500 newborns 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.

Epidemiology

  • Incidence
    • 1/1,000 newborns – profound deafness
      • 1/2,600 newborns – NSHL
        • Homozygous for GJB2 mutations – 50%
        • Compound heterozygous for GJB2 mutation and GJB6 deletion – 2-4%
        • Homozygous for GJB6 deletions – rare
        • Mitochondrial mutations – 1-2%
  • 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

  • GJB2 – autosomal recessive; rarely dominant
  • GJB6 – autosomal recessive; resulting from either 2 GJB6 deletions (rare) or 1 GJB6 deletion and 1 GJB2 mutation on the opposite chromosome
  • Mitochondrial DNA – dominant maternal inheritance
    • Hearing loss in some individuals with the 1555A>G mutation is 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

  • In general, sensorineural hearing loss with no other associated findings
  • GJB2 (Connexin 26) or GJB6 (Connexin 30) mutations – hearing loss is bilateral and stable with prelingual onset
  • Mitochondrial mutations often cause highly variable sensorineural hearing loss
    • Varies in severity and onset
    • m.7445 A>G mutation – palmar keratoderma and progressive, mild-to-severe hearing loss with childhood onset
    • m.1555A>G mutation – stable, severe-to-profound hearing loss with variable age of onset
      • May have predisposition to aminoglycoside ototoxicity
  • 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

Preferred first-tier genetic test for individuals with nonsyndromic hearing loss

Sensitivity – ~50% for all cases of NSHL

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

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

May be used as first-tier genetic test for individuals with nonsyndromic hearing loss

Sensitivity – ~45% for all cases of NSHL

 

GJB6 deletion testing is recommended if only one GJB2 mutation is identified

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

Most comprehensive genetic test at ARUP for hearing loss

Recommended first-tier testing for hearing loss or second-tier testing after GJB2, GJB6, and mitochondrial mutation testing has been performed

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

A negative result does not exclude a diagnosis of hereditary hearing loss

Not detected

  • Regulatory region mutations
  • Deep intronic mutations
  • Mutations in genes not targeted

Mitochondrial mutations associated with hearing loss will not be detected

Large deletions or duplications are not detected in ESPN, OTOA, and STRC genes, or in exon 5 of DNMT1 gene or exon 18 of DIAPH1 gene

Rare diagnostic errors can occur due to primer- or probe-site mutations

 
Expanded Hearing Loss Panel, Sequencing (56 Genes)  2008800
Method: Massive Parallel Sequencing

Recommended first-tier genetic test for hearing loss or second-tier testing after GJB2, GJB6, and mitochondrial mutation testing has been performed

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

A negative result does not exclude a diagnosis of hereditary hearing loss

Not detected

  • Regulatory region mutations
  • Deep intronic mutations
  • Mutations in genes not targeted

Mitochondrial mutations associated with hearing loss will not be detected

Rare diagnostic errors can occur due to primer- or probe-site mutations

 
Expanded Hearing Loss Panel, Deletion/Duplication (53 Genes) 2008808
Method: Exonic Oligonucleotide-based CGH Microarray

Recommended if Expanded Hearing Loss Panel, Sequencing (56 Genes) or equivalent test was negative or one autosomal recessive mutation was detected

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

A negative result does not exclude a diagnosis of hereditary hearing loss

Not detected

  • Regulatory region mutations
  • Deep intronic mutations
  • Mutations in genes not targeted

Mitochondrial mutations associated with hearing loss will not be detected

Large deletions or duplications are not detected in ESPN, OTOA, and STRC genes, or in exon 5 of DNMT1 gene or exon 18 of DIAPH1 gene

Rare diagnostic errors can occur due to primer- or probe-site mutations

 
Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions 2001956
Method: Polymerase Chain Reaction/Capillary Electrophoresis
Use only if Connexin 26 (GJB2) Sequencing detected one mutation in an affected individual, or if there is a known familial GBJ6 deletion

Detects only the two targeted GJB6 deletions

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

Use only if GJB2 and GJB6 testing is negative, or if there is a family history of mitochondrial mutation

2% sensitivity in individuals with NSHL

Detects only the two targeted mitochondrial mutations

 
Hearing Loss, Nonsyndromic, Connexin 26 (GJB2) 35delG Mutation 0051383
Method: Nucleic Acid Probe/Fluorescence Signal Amplification
Use only for individuals with a known family history of the GJB2 35delG mutation