Abstract
Background: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy, and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms.Methods and Results: Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with Autosomal dominant (AD) nonsyndromic late-onset hearing loss. Protein modeling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in α18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in α11 that causes a form of deafness with similar clinical characteristics.Conclusion: Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause AD nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24-related disorders. Three conserved residues in α18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease.
Highlights
Autosomal dominant (AD) nonsyndromic hearing loss (HL) is a heterogeneous condition regarding the age of onset, frequencies affected, progression, and severity
There was no history of syndromic neurologic disease, and brain magnetic resonance imaging (MRI) and neurological examinations showed no abnormalities in a member of the Austrian family (IV.8)
One member (IV.1) of the UK family had grommets fitted as a child because of perceived hearing difficulties which were attributed to ‘‘glue ear.’’ At 35 years of age, he had normal hearing up to 4,000 Hz but began to develop a bilateral, predominantly mild, high-frequency HL
Summary
Autosomal dominant (AD) nonsyndromic hearing loss (HL) is a heterogeneous condition regarding the age of onset, frequencies affected, progression, and severity. The high genetic and allelic heterogeneity of HL poses a challenge to the clinical assessment of novel variants routinely encountered during the diagnostic screening. TBC1D24, coding for TBC1 Domain Family Member 24, is a pleiotropic gene that has been associated with autosomal recessive (AR) HL (DFNB86), ADHL (DFNA65), and a range of epilepsy syndromes (Mucha et al, 2017). We report a novel (c.919A>C; p.Asn307His) mutation in TBC1D24 identified during WES and diagnostic panel screening of two unrelated ADHL families from Austria and the UK implying an association between AD HL disease phenotype and genetic variation affecting structural elements involved in phospholipid binding (Fischer et al, 2016). Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms
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