Deafness, Autosomal Dominant 3B (DFNA3B) and Deafness, Autosomal Recessive 1B (DFNB1B) via the GJB6 Gene

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the GJB6 gene are associated with prelingual, progressive, mild-to-severe high-frequency sensorineural hearing impairment. Audioprofiles may vary significantly, even within a family. No vestibular or temporal bone abnormalities are typically found (Smith et al. 1993).

The GJB6 gene encodes the gap junction protein beta 6, more commonly known as connexin 30. Connexins form gap junctions that facilitate metabolite and ion transport between adjacent cells. The role of connexin 30 in proper auditory function remains unclear, although it appears to be necessary for normal repair following sensory cell loss in the inner ear (Jagger and Forge 2015).

The different gene loci for nonsyndromic hearing loss are designated DFN (for DeaFNess) and named on the mode of inheritance; DFNA for autosomal dominant, DFNB for autosomal recessive and DFNX for X-linked inheritance, respectively. The GJB6 gene is located adjacent to the GJB2 gene in chromosomal region 13q12. GJB2 and GJB6 are both associated with nonsyndromic hearing loss inherited in both an autosomal dominant (DFNA3) and autosomal recessive (DFNB1) manner.

DFNA3 is caused by missense variants in either GJB2 (>90%) or GJB6 (<10%). DFNA3 has been further defined as DFNA3A (GJB2) and DFNA3B (GJB6). Both are characterized by prelingual, progressive, mild-to-severe high-frequency sensorineural hearing impairment, although DFNA3A is also reported to cause postlingual hearing loss (Smith et al. 1993). However, the association of GJB6 missense variants with DFNA3B remains uncertain due to limited evidence of dominant inheritance across multigenerational families (Grifa et al. 1999; Yang et al. 2007).

DFNB1 is caused by missense, nonsense, splicing and regulatory variants in GJB2 (~98%) or large deletions of GJB2 and/or upstream regions including GJB6 (~2%). DFNB1 has been further defined as DFNB1A (GJB2) and DFNB1B (GJB6). DFNB1 is characterized by congenital, non-progressive, mild to profound sensorineural hearing impairment. All DFNB1 documented pathogenic variants involving GJB6 are large deletions. Missense or nonsense variants in GJB6 have not been associated with DFNB1 (Smith et al. 1993).

Previous reports of individuals with hearing loss that were heterozygous for a variant in GJB2 and also heterozygous for a large deletion encompassing sequences upstream of GJB2 including all or part of GJB6 were thought to indicate digenic inheritance of DFNB1. However, subsequent experiments have shown that the mechanism of action of the deletions encompassing GJB6 is through altered GJB2 expression via loss of cis-regulatory elements in proximity to GJB6 (Rodriguez-Paris and Schrijver 2009; Rodriguez-Paris et al. 2011).

Aside from nonsyndromic hearing loss, pathogenic variants in the GJB6 gene can also cause Clouston syndrome or hidrotic ectodermal dysplasia, which is an autosomal dominant inherited skin disorder characterized by marked thickening of the palms and soles (palmoplantar hyperkeratosis), patchy or total hair loss (alopecia), thinning or thickening of nails (nail hypoplasia), as well as other nail deformities (Essenfelder et al. 2004).

This test provides full coverage of the single coding exon of the GJB6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.