Autosomal Recessive Hearing Loss
(DFNB1; Connexin 26 and Connexin 30)

Inheritance of NSHL (non-syndromic hearing loss): autosomal recessive; autosomal dominant (rare); digenic.

Incidence of NSHL: 1:1,000 newborns. Genetic cause in approx. 50%.

Pathophysiology: Connexin 26 (Cx26) and connexin 30 (Cx30) are gap junction proteins involved in potassium recycling in the inner ear.

Clinical features:
In many cases, the mutations lead to congenital deafness; however, phenotypic variability exists with milder forms of hearing loss; in such cases, patients may be able to develop speech.

Genetic cause:
Cx26 mutations are responsible in up to 63% of autosomal recessive NSHL cases (DFNB1). In these cases, the c.35delG mutation is predominantly found.
Sometimes, the affected persons are heterozygous for a single Cx26 mutation while no other mutation is detected. This might be attributable to the presence of pathogenic mutations outside the coding region (e.g. promoter region). Also, the persons in question might be carriers whose hearing loss is not caused by a Cx26 defect. Some cases are due to digenic inheritance, with additional presence of heterozygosity for a 342 kb deletion affecting a large portion of the 5’ region of the Cx30 gene. Cx30 is located 35 kb telomeric to Cx26 on chromosome 13.

Available diagnosis:

• Clinical:
  Audiology (sensorineural hearing loss).
  
• Molecular genetic testing:
  Direct sequencing of the Cx26 gene (1 exon, 2 amplicons).
  The Cx30 deletion is detected using PCR by which a junction fragment can be amplified – provided the deletion is present. Determination of this mode of inheritance is of particular importance in genetic counseling since it results in considerably higher recurrence rates of hearing loss in the offspring of patients as would be the case for autosomal recessive inheritance.
  

Gene, OMIM	Locus	Exons / Amplicons	Function	Proportion of DFNB %	Comments
Cx26 121011	13q12.11 (DFNB1)	1 cod. / 2	cell-to-cell contact; gap junction; K + recycling	63	Occasionally, Cx26 mutations cause autosomal dominant NSHL or, additionally, dermatologic manifestations (keratitis-ichthyosis-deafness syndrome)
Cx30 604418	13q12.11	1 cod. / 1 (junction fragment)	cell-to-cell contact; gap junction; K + recycling	low	342 kb deletion including a portion of Cx30, combined with a faulty Cx26 allele causes digenic hearing loss



• Genotype-phenotype correlation:
  Often deafness, but clinical severity may also differ between members of the same family.

Database:
Hereditary Hearing Loss Homepage
OMIM: see table

Since the genetic causes of hearing loss are one of our group’s key research areas, we are also interested in receiving samples of sporadic cases and of cases following other patterns of inheritance than autosomal recessive. These samples will be used in the investigation of candidate genes and for specific mutation analysis in certain hearing loss genes. Link to research site

References:
Petit C, Levilliers J, Hardelin JP. Molecular genetics of hearing loss. Ann Rev Genet 2001;35:589-646.
Bolz H, Schade G, Ehmer S, Kothe C, Hess M, Gal A. Phenotypic variability of non-syndromic hearing loss in patients heterozygous for both c.35delG of GJB2 and the 342-kb deletion involving GJB6. Hear Res 2004;188:42-46.

Contact: Hanno Bolz (see Staff)

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