title: Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations.
abstract: TBC1D24-related disorders include a wide phenotypic ranging from mild to lethal seizure disorders, non-syndromic deafness, and composite syndromes such as DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). The TBC1D24 gene has a role in cerebral cortex development and in presynaptic neurotransmission. Here, we present a familial case of a lethal early-onset epileptic encephalopathy, associated with two novel compound heterozygous missense variants on the TBC1D24 gene, which were detected by exome sequencing. The detailed clinical data of the three siblings is summarized in order to support the variability of the phenotype, severity, and progression of this disorder among these family members. Functional studies demonstrated that the identified novel missense mutations result in a loss of expression of the protein, suggesting a correlation between residual expression, and the disease severity. This indicates that protein expression analysis is important for interpreting genetic results when novel variants are found, as well as for complementing clinical assessment by predicting the functional impact. Further analysis is necessary to delineate the clinical presentation of individuals with TBC1D24 pathogenic variants, as well as to develop markers for diagnosis, prognosis, and potential targeted treatments. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departments of Genetic and Genomic Sciences, Psychiatry, and Pediatrics, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Reymundo
authors.initials: R
authors.lastname: Lozano
authors.affiliation: Department of Pediatrics, UC Davis Medical Center, Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, California.
authors.forename: Kristin
authors.initials: K
authors.lastname: Herman
authors.affiliation: Department of Pediatrics, UC Davis Medical Center, Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, California.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rothfuss
authors.affiliation: Departments of Genetic and Genomic Sciences, Psychiatry, and Pediatrics, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Hillary
authors.initials: H
authors.lastname: Rieger
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, Utah.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Aprile
authors.affiliation: Laboratory of Neurogenetics and Neuroscience, G. Gaslini Institute, Genova, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Fruscione
authors.affiliation: Laboratory of Neurogenetics and Neuroscience, G. Gaslini Institute, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.|Center of Synaptic Neuroscience and Technology, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fassio
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000503:physiopathology; D003638:Deafness / Q000235:genetics / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D009264:Nails, Malformed / Q000235:genetics* / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D010375:Pedigree; D035781:Siblings
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human
keywords: TBC1D24; deafness; lethal seizure disorder; neonatal seizure disorder; non-syndromic deafness; recessive seizures