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%
- 1/2,600 newborns – nonsyndromic hearing loss (NSHL)
- 1/1,000 newborns – profound deafness
- 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
- m.7445 A>G variant
- 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
Polymerase Chain Reaction/Capillary Electrophoresis/Sequencing
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
Polymerase Chain Reaction/Sequencing
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
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
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
Polymerase Chain Reaction/Capillary Electrophoresis
Panel includes GJB2 sequencing; GJB6 deletions; mitochondrial DNA, 2 variants; hearing loss panel specimen; hearing loss panel interpretation