Systematic multigene panel studies in hereditary hearing loss diagnose complex inheritance patterns involving multiple genes

 

Two sisters with rapid-onset dystonia-parkinsonism syndrome (RDP) were referred to us from paediatrics for hearing assessment. RDP is a rare autosomal dominant neurological disorder with episodes of dystonia, bradykinesia, and postural instability. Hearing dysfunction like the auditory neuropathy found in the genetically close related CAPOS syndrome has not yet been described in patients with RDP.

One sister (15 yrs) had near-normal thresholds, but objective audiometry (FAEP, OAE, ECochG) revealed a mild form of auditory neuropathy. The older sister (25 years) suffered from a moderate mid-frequency sensorineural hearing loss. Their mother (51 years) had progressive profound sensorineural hearing loss, predominantly affecting the middle and high frequencies.

We performed NGS multigene panel screening for mutations in 151 known deafness genes. Both sisters showed the RDP-causing mutation c.2267G>A in ATP1A3. An additional likely pathogenic sequence variant c.5510G>A in TECTA (class 4) was found in the older sister and the mother. The associated progressive cochlear hearing loss DFNA12 associated with this deafness gene is congruent with our audiological findings. Finally, both sisters were found to have another known pathogenic mutation, c.3503G>A, in MYO7A, which is associated with the age-related cochlear hearing loss DFNA11. This paternally inherited mutation currently contributes little to the phenotype but may become important with age.

In summary, the multigene panel study showed the simultaneous presence of three autosomal dominantly inherited diseases affecting the phenotype of this family: the maternally inherited DFNA12 in the older sister, the paternally inherited DFNA11 to both sisters, and the RDP inherited to both sisters from a gonadal mosaic of the mother.

Publication History

Article published online:
24 May 2022

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