Deafness, Autosomal Recessive 63 (DFNB63) via the LRTOMT Gene

Deafness, autosomal recessive 63 (DFNB63) is a prelingual, bilateral, nonprogressive, nonsyndromic, sensorineural hearing loss disorder with variable frequency impairment, wherein some may show impairment to all frequencies, whereas others only involve mid- to high frequencies (Tlili et al. 2007). 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). Pure tone audiograms of DFNA63 individuals generally show gently downward-sloping to flat pure tone audiograms, indicating mid-/high-frequency to all-frequency hearing impairment (Ichinose et al. 2015). DFNB63 patients show no signs of vestibular dysfunction or skin, renal, or optic anomalies.

DFNA63 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the leucine-rich transmembrane O-methyltransferase (LRTOMT) gene (previously called leucine-rich repeat-containing protein 51 (LRRC51), which is located on chromosome 11q13.4 (Ahmed et al. 2008). The LRTOMT gene consists of 10 coding exons and generates two alternative reading frames, thus encoding two different proteins, namely LRTOMT1 and LRTOMT2, which differ by their translation start codons. LRTOMT1 is encoded when translation starts in exon 3, and has a predicted transmembrane domain and two leucine-rich repeats. LRTOMT2 is encoded when translation begins in exon 5, and is predicted to comprise a catechol-O-methyltransferase domain (Ahmed et al. 2008). The LRTOMT1 protein is most prominently expressed along the basolateral wall of outer hair cells and distributed throughout the cytoplasm, thereby providing structural support (Ahmed et al. 2008). The LRTOMT2 protein is also highly expressed in sensory hair cells of the inner ear and is essential for auditory and vestibular function (Du et al. 2008). To date, a total of about 15 pathogenic LRTOMT sequence variants have been reported, all of which exclusively affect the LRTOMT2 protein. These include 10 missense and 2 protein truncating sequence variants, 1 splicing variant and 2 small deletions (Vanwesemael et al. 2011; Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range up to 2%. For example, in Iran, 0.7% (1/144) of families with autosomal recessive nonsyndromic hearing loss carried disease-causing sequence variants in the LRTOMT gene (Babanejad et al. 2012). In Japan, 0.9% (1/106) patients with sensorineural hearing loss from nonconsanguineous families showed causative LRTOMT sequence variants (Ichinose et al. 2015). In Turkey, 2% (1/49) of consanguineous families with nonsyndromic hearing loss tested positive for causative variants in the LRTOMT gene (Duman et al. 2011).

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