Deafness, X-Linked 4 (DFNX4) via the SMPX 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 SMPX gene is associated with postlingual, bilateral, moderate to profound, progressive sensorineural hearing impairment beginning in the high frequencies. No vestibular abnormalities are present (Huebner et al. 2011; Schraders et al. 2011; Weegerink et al. 2011).

DFNX4 is a sex-linked dominant hearing disorder that is caused by pathogenic sequence variants in the small muscle protein, X-linked (SMPX) gene, which is located on chromosome Xp22.12 .Age of onset is in the first decade for males and first to fourth decade for females. In female carriers penetrance is incomplete with 70% of individuals showing moderate to severe hearing loss at high frequencies by the fourth decade (Weegerink et al. 2011).

The SMPX gene spans 56 kb and consists of 3 coding exons that produce a 88 amino acid protein. The SMPX gene is expressed in fetal and adult skeletal muscle and heart, fetal inner ear and adult retina. The exact role of the SMPX protein in inner ear function remains unknown, although it is thought to be involved in the development and/or maintenance of the sensory hair cells through association with the cytoskeleton (Huebner et al. 2011; Schraders et al. 2011).

Missense, nonsense, splicing and small deletion variants in SMPX have been reported as pathogenic for hearing loss, with about 10 variants reported to date in different families showing X-linked inheritance (Human Gene Mutation Database).

In a study of 1,119 patients with hearing loss in which 440 patients received a genetic diagnosis, only two pathogenic variants in the SMPX gene were detected (Sloan-Heggen et al. 2016). Missense, nonsense, splicing and small deletion variants in SMPX have been reported as pathogenic for hearing loss, with about 10 variants reported to date in different families showing dominant X-linked inheritance (Human Gene Mutation Database). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

The clinical sensitivity of CNV detection is unknown. No large deletion or duplication variants associated with SMPX have been reported as pathogenic for hearing loss.

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