Hereditary Nonsyndromic Hearing Loss - 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 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