Abstract
Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband's mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy.
Highlights
Mutations in the TBC1D24 gene are the cause of multiple rare disorders whose phenotype consists of varying degrees of intellectual disability, deafness, cortical malformations, and/or epilepsy[1]
We describe a single family in which TBC1D24 mutations cause both dominant and recessive phenotypes: dominant tonic-clonic and myoclonic epilepsy, and a recessive severe disorder with epilepsy, Parkinsonian tremor, intellectual disability and psychosis
Exome sequencing in the proband and parents led to the identification of compound heterozygote mutations in TBC1D24 in the patient (II:1), p.Pro135Leu; c.404C>T in exon 2 and p.Arg360Cys; c.1078C>T in exon 4 (NM_001199107.1) (Figure 1)
Summary
Mutations in the TBC1D24 gene are the cause of multiple rare disorders whose phenotype consists of varying degrees of intellectual disability, deafness, cortical malformations, and/or epilepsy[1]. The disorders caused by TBC1D24 dysfunction make up a continuum of six distinct phenotypes that include DOORS syndrome (Deafness, Onochydystrophy, Osteodystrophy, mental Retardation and Seizures; autosomal recessive; AR), familial infantile myoclonic epilepsy (FIME; AR), progressive myoclonus epilepsy (PME; AR), early-infantile epileptic encephalopathy (EIEE16; AR), autosomal recessive non-syndromic hearing loss (DFNB86; AR), and autosomal dominant non-syndromic hearing loss (DFNA65; AD). Drosophila with mutations in the sky gene (TBC1D24 orthologue) have a larger readily releasable pool of synaptic vesicles and show a dramatic increase in basal neurotransmitter release[3]. We describe a single family in which TBC1D24 mutations cause both dominant and recessive phenotypes: dominant tonic-clonic and myoclonic epilepsy, and a recessive severe disorder with epilepsy, Parkinsonian tremor, intellectual disability and psychosis. We discuss and highlight for the first time that dominant inheritance of TBC1D24 mutations might be associated with epilepsy
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