Hereditary Nonsyndromic Hearing Loss - 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

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%
  • 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
  • No other anatomic defects are typically present

ARUP Laboratory Tests

First-tier genetic test for individuals with nonsyndromic hearing loss (NSHL)

Refer to the Test Fact Sheet for a list of limitations

Panel includes GJB2 sequencing; GJB6 deletions; mitochondrial DNA, 2 variants; hearing loss panel specimen; hearing loss panel interpretation

Diagnostic testing or carrier screening for GJB2-related NSHL

May be used as first-tier genetic test for individuals with NSHL

Refer to the Test Fact Sheet for a list of limitations

Most comprehensive genetic test for NSHL and syndromic hearing loss

Recommended test for NSHL if GJB2, GJB6, and mitochondrial variant testing is negative

Recommended test for syndromic hearing loss if symptoms are consistent with disorders included on panel

Refer to the Test Fact Sheet for a list of genes tested

Refer to the Test Fact Sheet for a list of limitations

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

Refer to the Test Fact Sheet for a list of limitations

Test Fact Sheet(s)

Medical Experts

Contributor

Baldwin

Erin Baldwin, MS, LCGC
Manager, Genetic Counselor Services, ARUP Laboratories
Contributor

Mao

Rong Mao, MD, FACMG
Professor of Clinical Pathology, University of Utah
Section Chief, Molecular Genetics and Genomics, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®