Submission Details

Autosomal recessive TBC1D24-related syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness, to benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct phenotypic correlation with pathogenic variant type or location yet, but patterns are emerging (Balestrini 2016). Sensorineural hearing loss is a key feature of DOORS syndrome, which is characterized by deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (Campeau 2014). Isolated seizure disorders without any reported deafness have been seen (Balestrini 2016). In contrast, two of the families reported to have nonsyndromic hearing loss caused by variants in TBC1D24 were shown to have no history of seizures (Rehman 2014). Further, two independent reports identified the same variant in TBC1D24 to be segregating in an autosomal dominant manner with nonsyndromic hearing loss (Azaiez 2014, Zhang 2014). The strength of the evidence that this gene can cause autosomal dominant nonsyndromic hearing loss is Limited, however. Currently there is not enough evidence to treat nonsyndromic hearing loss or isolated seizures as distinct conditions, especially because those affected with DOORS syndrome have both hearing loss and seizure phenotypes. Experimental evidence has implicated a role for the TBC1D24 gene in neuronal development, including neurite length and arborization (Corbett 2010, Falace 2010, Milh 2013) as well as in protection from neuronal oxidative stress (Finelli 2016). While the gene has been shown to be expressed in the murine cochlea (Rehman 2014, Azaiez 2014, Zhang 2014) , there is no further evidence for a potential mechanism of hearing loss. In summary, the TBC1D24 gene is definitively associated with a spectrum of autosomal recessive phenotypes which the Hearing Loss and Epilepsy Gene Curation Expert Panels propose are a spectrum of DOORS syndrome. This classification was approved by both the ClinGen Hearing Loss and Epilepsy Working Groups on 3/19/19 (SOP Version 6).