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.

Tabs Content

Clinical Overview

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 Lab Tests

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

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

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

Refer to Additional Technical Information document for further content

Clinical sensitivity – 50-55% for Caucasians with NSHL; unknown in other ethnicities

Limitations

A negative result does not exclude a diagnosis of hereditary hearing loss

Diagnostic errors can occur due to rare sequence variations

GJB2 regulatory region variants, deep intronic variants, and large deletions or duplications will not be detected

GJB6 and mitochondrial DNA variants, aside from those targeted, will not be detected

Etiology of hearing loss due to other genetic or environmental causes will not be determined

Small deletions or insertions may not be detected by massively parallel sequencing

In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes, repetitive, or homologous region

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

Recommended Use

Diagnostic testing or carrier screening for GJB2-related NSHL

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

Clinical sensitivity – 95% of GJB2 pathogenic variants are detected

Limitations

A negative result does not exclude a diagnosis of hereditary hearing loss

Diagnostic errors can occur due to rare sequence variations

Large GJB2 gene deletions or deep intronic variants will not be identified

Hearing loss caused by other genetic or environmental causes will not be detected

Small deletions or insertions may not be detected by massively parallel sequencing

In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes, repetitive, or homologous region

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 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

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

Limitations

A negative result does not exclude a diagnosis of hereditary hearing loss

Regulatory region variants, deep intronic variants, variants in genes not targeted, large deletions or duplications in ESPN, OTOA, and STRC genes, or in exon 5 of DNMT1 gene or exon 18 of DIAPH1 gene will not be detected

Small deletions or insertions may not be detected by massively parallel sequencing

Due to the high homology with pseudogenes some of the functional gene variants in the ADGRV1, DSPP, ESPN, KCNQ4, MYO15A, STRC, TRIOBP, and WSF1 genes may be missed

In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes, repetitive, or homologous region

Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions 2001956
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Recommended Use

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 Additional Technical Information document for further content

Limitations

A negative result does not exclude a diagnosis of hereditary hearing loss

GJB6 variants other than 2 targeted will not be identified

Etiology of hearing loss due to other genetic or environmental causes will not be determined

Diagnostic errors can occur due to rare sequence variations

Small deletions or insertions may not be detected by massively parallel sequencing

In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes, repetitive, or homologous region

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

Recommended Use

Diagnostic test for individuals with NSHL and no identified variants in GJB2 or GJB6

Carrier screening if family history of m.1555A>G or m.7445A>G

Limitations

A negative result does not exclude a diagnosis of hereditary hearing loss

Diagnostic errors can occur due to rare sequence variations

Variants other than 2 targeted will not be identified

Etiology of hearing loss due to other genetic or environmental causes will not be determined

Small deletions or insertions may not be detected by massively parallel sequencing

In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes, repetitive, or homologous region

Medical Reviewers

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

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

References

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

Last Update: March 2018


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Hereditary Nonsyndromic Hearing Loss - Connexin 26 or 30

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Inheritance

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Reviewers

References

General References