Deafness, Autosomal Dominant 36 (DFNA36) and Deafness, Autosomal Recessive 7 (DFNB7) via the TMC1 Gene

Autosomal dominant deafness 36 (DFNA36) is characterized by flat or gently downsloping, progressive, postlingual, sensorineural nonsyndromic hearing loss (Kurima et al. 2002). This disorder generally starts within the first two decades of life, eventually progressing to profound deafness within 10 to 15 years (Hilgert et al. 2009; Zhao et al. 2014). Autosomal recessive deafness 7 (DFNB7) is characterized by severe to profound, stable, prelingual, sensorineural nonsyndromic hearing loss (Scott et al. 1996). The audioprofile of most 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).

DFNA36, an autosomal dominant hearing disorder, and DFNB7, an autosomal recessive hearing disorder, are caused by pathogenic sequence variants in the transmembrane channel-like (TMC1) gene, which is a member of the novel TMC gene family. Seven other TMC1 paralogs have been detected in various mammalian species (Davies et al. 2012). The TMC1 gene has been localized to chromosomal region 9q13-q21 and consists of 24 exons (Scott et al. 996). The function of the TMC1 protein remains obscure, although in silico analysis predicts that it is an integral membrane protein with six membrane-spanning domains (Drury et al. 2003). This protein topology has been confirmed in hair cells of the mouse inner ear, thus suggesting that it functions as a channel, receptor, or pump (Kawashima et al. 2011; Zhao et al. 2014). To date, a total of about 60 pathogenic TMC1 sequence variants have been reported, which include missense/nonsense, splicing, regulatory, small deletions, small insertions, and gross deletions (Human Gene Mutation Database). Only two dominant pathogenic sequence variants have been reported in the TMC1 gene (p.G417R and p.D572N), and studies have suggested that these variants cause disease in a dominant-negative or gain-of-function mechanism, instead of haploinsufficiency. Pathogenic missense variants at other positions in the gene apparently result in the creation of a functional null allele that would only cause hearing loss in the compound heterozygous or homozygous state (Kurima et al. 2002; Yang et al. 2010).

Reported clinical sensitivity of the TMC1 test ranges from 0.1% to 8%. For example, in Japan, 0.09% (1/1,120) of nonsyndromic hearing loss cases were caused by pathogenic sequence variants in the TMC1 gene (Nishio and Usami 2015). In a Pakistani study, 3.3% (1/30) of families with autosomal recessive nonsyndromic hearing loss harbored disease-causing TMC1 sequence variants (Shafique et al. 2014). On the other hand, pathogenic TMC1 sequence variants were detected in 5% (1/20) of consanguineous families with autosomal recessive nonsyndromic hearing loss from Turkey and Iran (Diaz-Horta et al. 2012). In another study conducted in Turkey, 8% (4/49) of consanguineous families with nonsyndromic deafness were determined to harbor causative variants in the TMC1 gene (Duman et al. 2011).

This test provides full coverage of all coding exons of the TMC1 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).