A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24

Mark A. Corbett, Melanie Bahlo, Lachlan Jolly, Zaid Afawi, Alison E. Gardner, Karen L. Oliver, Stanley Tan, Amy Coffey, John C. Mulley, Leanne M. Dibbens, Walid Simri, Adel Shalata, Sara Kivity, Graeme D. Jackson, Samuel F. Berkovic, Jozef Gecz

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

We 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.

Original languageEnglish
Pages (from-to)371-375
Number of pages5
JournalAmerican Journal of Human Genetics
Volume87
Issue number3
DOIs
Publication statusPublished - 10 Sep 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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