Bahlo, M.Jolly, L.Afawi, Z.Gardner, A.Oliver, K.Tan, S.Coffey, A.Mulley, J.Dibbens, L.Simri, W.Shalata, A.Kivity, S.Jackson, G.Berkovic, S.Gecz, J.Corbett, M.2011-02-072011-02-072010American Journal of Human Genetics, 2010; 87(3):371-3750002-92971537-6605http://hdl.handle.net/2440/62378We characterized an autosomal-recessive syndrome of focal epilepsy, dysarthria, and mild to moderate intellectual disability in a consanguineous Arab-Israeli family associated with subtle cortical thickening. We used multipoint linkage analysis to map the causative mutation to a 3.2 Mb interval within 16p13.3 with a LOD score of 3.86. The linked interval contained 160 genes, many of which were considered to be plausible candidates to harbor the disease-causing mutation. To interrogate the interval in an efficient and unbiased manner, we used targeted sequence enrichment and massively parallel sequencing. By prioritizing unique variants that affected protein translation, a pathogenic mutation was identified in TBC1D24 (p.F251L), a gene of unknown function. It is a member of a large gene family encoding TBC domain proteins with predicted function as Rab GTPase activators. We show that TBC1D24 is expressed early in mouse brain and that TBC1D24 protein is a potent modulator of primary axonal arborization and specification in neuronal cells, consistent with the phenotypic abnormality described.en© 2010 The American Society of Human GeneticsNeuronsAxonsAnimalsHumansMiceEpilepsies, PartialSyndromeGTPase-Activating ProteinsCarrier ProteinsMembrane ProteinsNerve Tissue ProteinsChromosome MappingPedigreeCell ShapeAmino Acid SequenceMutationOpen Reading FramesMolecular Sequence DataInfantFemaleMaleIntellectual DisabilityJournal article002010102610.1016/j.ajhg.2010.08.0010002819235000062-s2.0-7795639412633200Jolly, L. [0000-0003-4538-2658]Gardner, A. [0009-0009-7321-1697]Gecz, J. [0000-0002-7884-6861]Corbett, M. [0000-0001-9298-3072]