Deafness, Autosomal Recessive 67 (DFNB67) via the LHFPL5 Gene

Autosomal recessive deafness 67 (DFNB67) is characterized by prelingual, bilateral, severe to profound, stable, sensorineural nonsyndromic hearing loss but without vestibular abnormalities (Kalay et al. 2006). Most DFNB67 individuals are born to consanguineous parents (Kalay et al. 2006).

DFNB67 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also known as the tetraspan membrane protein of hair cell sterocilia (TMHS) gene, which is located on chromosome 6p21.31 (Shabbir et al. 2006). The LHFPL5 gene consists of three coding exons that produce a 219-amino acid protein, which consists of four transmembrane domains and two connecting extracellular loops (Kalay et al. 2006). The LHFPL5 protein is mainly expressed in the stereocilia of the inner and outer hair cells of the inner ear (Longo-Guess et al. 2005). The LHFPL5 protein serves as an integral component of the mechanotransduction machinery of the cochlea, particularly the stereocilia, where it interacts with the cochlear protein protocadherein-15, which is responsible for applying force to the mechanotransduction channel (Beurg et al. 2015).

Mutational studies involving the 'hurry-scurry' (hscy) mouse model showed that pathogenic sequence variants in the LHFPL5 gene cause severe degeneration of the organ of Corti, thereby resulting in the absence of response to auditory stimuli, as well as circling behavior, constant head shaking from side to side, and the inability to swim (Longo-Guess et al. 2005). A similar phenotype was observed in Drosophila animal models with pathogenic sequence variants in the TMHS gene (Cosetti et al. 2008). To date, less than 10 pathogenic LHFPL5 variants have been reported. These variants are a mix of in-frame (missense) and chain termination (frameshift, splicing) variants (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 0.5% to 1.5%. In Japan, 0.5% (1/216) of Japanese deafness patients harbored causative sequence variants in the LHFPL5 gene (Miyagawa et al. 2013). In Algeria, 1.5% (1/65) of families affected by autosomal recessive nonsyndromic hearing impairment and tested negative for pathogenic sequence variants in the GJB2 gene were determined to have disease-causing LHFPL5 variants (Ammar-Khodja et al. 2015).

This test provides full coverage of all coding exons of the LHFPL5 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).