Deafness, Autosomal Dominant 20 (DFNA20) via the ACTG1 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 ACTG1 gene is associated with postlingual, bilateral, moderate to profound, progressive sensorineural hearing impairment beginning in the high frequencies. No vestibular abnormalities are present (Zhu et al. 2003).

DFNA20 is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the actin gamma 1 (ACTG1) gene, which is located on chromosome 17q25.3. The ACTG1 gene spans 6.9 kb and consists of 5 coding exons that produce a 375 amino acid protein. The exact role of the ACTG1 protein in inner ear function remains unknown, although variants in many actin-interacting proteins are also known to cause hearing loss (Zhu et al. 2003).

Only missense variants in ACTG1 have been reported as pathogenic for hearing loss, with >15 variants reported to date in different families (Human Gene Mutation Database). Missense variants in ACTG1 have also been reported to cause Baraitser-Winter syndrome 2, characterized by distinct craniofacial features, ocular coloboma and neuronal migration defect (Rivière et al. 2012).

The clinical sensitivity of this sequencing test is not precisely known. More than 15 missense variants in ACTG1 have been reported as pathogenic for hearing loss in different families (Human Gene Mutation Database). However, screening of 19 Norwegian and Danish families with autosomal dominant hearing loss did not identify any pathogenic variants in ACTG1 (Rendtorff et al. 2006), suggesting ACTG1 is not a common cause of autosomal dominant hearing loss. Analytical sensitivity should be high because all reported variants are detectable by sequencing.

This test provides full coverage of all coding exons of the ACTG1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).