Hearing Loss, Hereditary Nonsyndromic - Connexin 26 or 30

  • 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 mutation

Laboratory Testing

  •  Recommended triad – ~50% sensitivity for all NSHL
    • GJB2 sequencing
    • GJB6 targeted deletion testing
    • Mitochondrial testing for 2 mutations

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, MELAS)
  • Autoimmune hearing loss

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 1GJB2 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
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

Recommended Use 

Diagnostic testing for individuals with nonsyndromic hearing loss (NSHL)

Recommended for individuals who have not had prior testing to determine the etiology for NSHL

Panel includes GJB2 sequencing, GJB6 deletions, mitochondrial DNA, 2 mutations, hearing loss panel interpretation

Refer to Additional Technical Information document for further content

Clinical sensitivity – dependent on tests and ethnicity

Analytical sensitivity/specificity – >99%

Limitations 

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

The etiology of hearing loss caused by other genetic or environmental causes will not be determined

Rare diagnostic errors can occur due to rare sequence variations

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

Recommended Use 

Diagnostic testing or carrier screening for GJB2-related NSHL

Clinical sensitivity – dependent on tests and ethnicity

Analytical sensitivity/specificity – >99%

Follow-up 

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: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended Use 

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

Genes include – ACTG1, CCDC50, CDH23, CEACAM16, CLDN14, CLRN1, COCH, COL11A2, CRYM, DFNA5, DFNB31, PJVK, DIAPH1, DNMT1, DSPP, ESPN, ESRRB, EYA4, GJB2 (connexin 26), GJB3, GJB6 (connexin 30), GPR98, GPSM2, GRHL2, HARS2, HSD17B4, KCNQ4, LHFPL5, MARVELD2, MASP1, MYH14, MYH9, MYO15A, MYO1A, MYO3A, MYO6, MYO7A, OTOA, OTOF, PCDH15, POU4F3, RDX, SLC26A4, SLC26A5, SMPX, STRC, TECTA, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C, USH1G, USH2A, WFS1

Refer to Additional Technical Information document for further content

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

Limitations 

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, large deletions or duplications 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: Massively Parallel Sequencing

Recommended Use 

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

Genes include – ACTG1, CCDC50, CDH23, CEACAM16, CLDN14, CLRN1, COCH, COL11A2, CRYM, DFNA5, DFNB31, PJVK, DIAPH1, DNMT1, DSPP, ESPN, ESRRB, EYA4, GJB2 (connexin 26), GJB3, GJB6 (connexin 30), GPR98, GPSM2, GRHL2, HARS2, HSD17B4, KCNQ4, LHFPL5, MARVELD2, MASP1, MYH14, MYH9, MYO15A, MYO1A, MYO3A, MYO6, MYO7A, OTOA, OTOF, PCDH15, POU4F3, RDX, SLC26A4, SLC26A5, SMPX, STRC, TECTA, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C, USH1G, USH2A, WFS1

Refer to Additional Technical Information document for further content

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

Limitations 

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

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 Use 

Recommended if expanded hearing loss panel, sequencing (56 Genes) or equivalent test was negative or one autosomal recessive mutation was detected

Genes include – ACTG1, CCDC50, CDH23, CEACAM16, CLDN14, CLRN1, COCH, COL11A2, CRYM, DFNA5, DFNB31, PJVK, DIAPH1, DNMT1, DSPP, ESRRB, EYA4, GJB2 (connexin 26), GJB3, GJB6 (connexin 30), GPR98, GPSM2, GRHL2, HARS2, HSD17B4, KCNQ4, LHFPL5, MARVELD2, MASP1, MYH14, MYH9, MYO15A, MYO1A, MYO3A, MYO6, MYO7A, OTOF, PCDH15, POU4F3, RDX, SLC26A4, SLC26A5, SMPX, TECTA, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C, USH1G, USH2A, WFS1

Refer to Additional Technical Information document for further content

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – 98%

Limitations 

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, large deletions or duplications 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

Recommended Use 

For individuals with NSHL and only 1 identifiable GJB2 mutation identified by sequencing

Carrier screening if family history of GJB6 deletion

Carrier screening for reproductive partner of individual with GJB6 or GJB2 mutation(s)

Refer to Additional Technical Information document for further content

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – >99%

Limitations 

Detects only the two targeted GJB6 deletions

The etiology of hearing loss caused by other genetic or environmental causes will not be determined

Rare diagnostic errors can occur due to rare sequence variations

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

Recommended Use 

Use for individuals with nonsyndromic hearing loss and no identified mutations in GJB2 or GJB6 by sequencing or deletion testing

Detect mitochondrial mutations − m.1555A>G and m.7445A>G

Clinical sensitivity/specificity – depends on disorder

Analytical sensitivity/specificity – >99%

Limitations 

Detects only the two targeted mitochondrial mutations

The etiology of hearing loss caused by other genetic or environmental causes will not be determined

Rare diagnostic errors can occur due to rare sequence variations

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

Baldwin, Erin, MS, LCGC, Genetic Counselor, Molecular Genetics, Cytogenetics, and Maternal Serum Screening at ARUP Laboratories

Mao, Rong, MD, Medical Director, Molecular Genetics and Genomics at ARUP Laboratories; Associate Professor of Clinical Pathology and Co-director, Clinical Medical Genetics Fellowship Program, University of Utah

Last Update: August 2016

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