Deafness, Autosomal Dominant 2A (DFNA2A) via the KCNQ4 Gene

Deafness, Autosomal dominant 2A (DFNA2A) is characterized by progressive, postlingual, symmetric, sensorineural nonsyndromic hearing loss (Coucke et al. 1999). The audioprofile of most autosomal dominant nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008). Pure tone audiometry indicates that DFNA2A generally develops during adolescence or the early 20s and initially only involves high-frequency hearing impairment, which then later progresses to profound all-frequency hearing loss (Nie 2008).

DFNA2A is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the KCNQ4 gene. KCNQ4 is mainly expressed in the sensory outer hair cells of the cochlea and neurons of the central auditory pathway, and plays a major role in regulating electrical signaling and ionic composition of biologic fluids (Kharkovets et al. 2000). The KCNQ4 gene is located within chromosomal region 1p34 and consists of 14 exons that encode a 695-amino acid protein comprising six transmembrane domains and a P-loop region that forms a potassium-selective channel pore (Coucke et al. 1994; Kubisch et al. 1999).

To date, a total of about 30 pathogenic KCNQ4 sequence variants have been reported, which include missense/nonsense, splicing, small deletions, and small insertions (Human Gene Mutation Database). Previous studies have shown that patients with missense sequence variants in the KCNQ4 gene have earlier disease onset and more profound hearing loss, thereby reflecting a dominant-negative effect, whereas individuals with chain termination KCNQ4 sequence variants generally present late-onset, milder, and pure high-frequency hearing loss, which is indicative of haploinsufficiency (Kamada et al. 2006).

The clinical sensitivity of this test has been reported to range from about 1 to 6%. For example, disease-causing KCNQ4 variants were detected in 0.8% (1/12) of Taiwanese patients with nonsyndromic deafness (Wu et al. 2013). In two studies involving Japanese deafness patients, 1% (3/216 and 1/1,120) harbored causative KCNQ4 sequence variants (Miyagawa et al. 2013; Nishio and Usami 2015). Another two investigations conducted in Japan indicated that pathogenic sequence variants in the KCNQ4 gene accounted for 6% (1/16 and 19/287) of Japanese families with autosomal dominant nonsyndromic hearing loss (Akita et al. 2001; Naito et al. 2013).

This test provides full coverage of all coding exons of the KCNQ4 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).