Hearing Loss, Hereditary Nonsyndromic

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 has NSHL due to 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 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 is induced by aminoglycosides

Pathophysiology

Pathogenic mutations in GJB1, GJB2, GJB3, or GJB6 genes are known to cause 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 associated with palmar keratoderma and progressive, mild-to-severe hearing loss with childhood onset
- m.1555A>G associated with stable, severe-to-profound hearing loss with variable age of onset
No other anatomic defects are typically present

Indications for Testing

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

Tests generally appear in the order most useful for common clinical situations

Test name: Hearing Loss, Nonsyndromic Panel (GJB2) Sequencing, (GJB6) 2 Deletions and Mitochondrial DNA 2 Mutations

ARUP #: 2001992

Methodology: Polymerase Chain Reaction/Capillary Gel Electrophoresis/Sequencing

Use: Identify the common causes of NSHL in GJB2, GJB6 and mitochondrial DNA

Limitations:

Only GJB2 sequence variants, two targeted GJB6 deletions and two targeted mitochondrial mutations will be detected

Sensitivity is ~50% for all cases of NSHL

Test name: Connexin 26 (GJB2), Sequencing

ARUP #: 0051374

Methodology: DNA Probe/Fluorescence Signal Amplification/Polymerase Chain Reaction/Sequencing

Use:

Identify 95% of GJB2 gene mutations

Limitations:

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

Follow-up:

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

Test name: Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions

ARUP #: 2001956

Methodology: Polymerase Chain Reaction/Capillary Gel Electrophoresis

Use:

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

Limitations:

Only the two targeted GJB6 deletions will be detected

Test name: Hearing Loss, Nonsyndromic, Mitochondrial DNA 2 Mutations

ARUP #: 2002044

Methodology: Polymerase Chain Reaction/Sequencing

Use: Identify common mitochondrial mutations

Limitations:

Only the two targeted mitochondrial mutations will be detected

2% sensitivity in individuals with NSHL

Test name: Hearing Loss, Nonsyndromic, Connexin 26 (GJB2) 35delG Mutation

ARUP #: 0051383

Methodology: DNA Probe and Fluorescent Signal Amplification

Use: Screening for 35delG/GJB2 mutation common in Caucasians if previously identified in another family member

Limitations:

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

General

Comprehensive Review: July 2011
Last Update: July 2011

Alport Syndrome

Autoimmune Inner Ear Disease

Cogan Syndrome