Abstract
Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts.
Highlights
The TBC1D24 gene (OMIM #613577) encodes a family of Tre2-Bub2-Cdc16 (TBC) domain containing RAB-specific GTPase-activating proteins, which are thought to be involved in exoand endo-cytosis of vesicles [1, 2]
Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS and non-syndromic hearing loss (NSHL)
Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation
Summary
The TBC1D24 gene (OMIM #613577) encodes a family of Tre2-Bub2-Cdc (TBC) domain containing RAB-specific GTPase-activating proteins, which are thought to be involved in exoand endo-cytosis of vesicles [1, 2]. TBC1D24 expression is present in the cochlea in the inner and outer hair cells and in the spiral ganglion neurons [5, 6], substantiating why TBC1D24 mutations can induce hearing loss. Using whole exome sequencing (WES) on probands from recessive families without genetic diagnosis, we identified two pedigrees with compound heterozygote mutations in TBC1D24, which prompted further sequencing of all TBC1D24 exons in the 62 families devoid of molecular genetic diagnosis. This led to the identification of an additional simplex case, again with compound heterozygote mutations
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