Abstract
Sensorineural hearing loss (SNHL) is a heterogeneous family of hearing disabilities with congenital (including genetic) as well as acquired etiology. Congenital SNHL of genetic etiology is further sub-divided into autosomal dominant, autosomal recessive and X-linked SNHL. More than 60 genes are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL) commonly manifesting as heterogeneous pre-lingual profound to severe non-progressive clinical phenotype. ILDR1-dependent ARNSHL (DFNB42, OMIM: # 609646) is a very rare sub-type of hearing disability, with unknown prevalence, caused by function-damaging genetic variants in ILDR1 gene reported in families of Middle-Eastern origin. ILDR1 (Immunoglobulin-Like Domain-containing Receptor 1) is involved in the development of semicircular canal, tricellular tight junction and auditory hair cells. An apparently non-consanguineous family of European ancestry with two affected siblings with profound progressive hearing loss characterized in their infancy and successfully treated with cochlear implants (CI) is presented. Genetic analysis of common ARNSHL genetic causes in the population of origin was negative, thus the next-generation sequencing (NGS) and family segregation analysis to identify underlying causative genetic variant was performed. Unexpectedly and atypical for the population of origin a homozygous non-sense variant ILDR1 c.942C > A (p.Cys314Ter) inherited from both heterozygous parents was identified in both patients. Contrary to the commonly reported phenotype, indices of a progressive hearing loss and potential compensatory mechanism of vestibular function were revealed with the analysis of clinical data. The utilization of NGS was demonstrated as an invaluable tool for the detection of atypical rare variants in diagnostics of unidentified hearing loss disorders.
Highlights
Sensorineural hearing loss (SNHL) is a family of heterogeneous conditions spanning acquired as well as congenital causes of the disease
GJB2 mutations are responsible for approximately 27% and TMPRSS3 mutations are responsible for around 13% of remaining Slovenian autosomal recessive non-syndromic hearing loss (ARNSHL) population (Battelino et al, 2015)
The advent of generation sequencing and its introduction into routine genetic diagnostic procedures accelerated the identification of causative genetic variants across heterogeneous population of patients with SNHL (Diaz-Horta et al, 2012; Yan et al, 2013)
Summary
Sensorineural hearing loss (SNHL) is a family of heterogeneous conditions spanning acquired as well as congenital causes of the disease. More than 60 genes (Van Camp and Smith, 2017) are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL), which phenotype is usually profound to severe, non-progressive and pre-lingual (Petersen and Willems, 2006). The advent of generation sequencing and its introduction into routine genetic diagnostic procedures accelerated the identification of causative genetic variants across heterogeneous population of patients with SNHL (Diaz-Horta et al, 2012; Yan et al, 2013). Loss-of-function ILDR1 mutations have been implicated in the development of very rare non-syndromic autosomal recessive deafness type 42 (DFNB42) in humans (Borck et al, 2011). The functional characterization of identified ILDR1 variants in mouse mammary epithelial EpH4 cell lines revealed the disruption of tricellulin (a component of tricellular tight junction) recruitment by ILDR1 and failure to form tight junction (Kim et al, 2015)
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