Abstract:

Microdeletions encompassing the 2p14 region have been reported to cause a novel microdeletion syndrome, characterised by mild intellectual disability (ID) and language impairment (LI), usually showing no congenital malformations or severe dysmorphisms. Actin-related protein 2 (ACTR2) and Ras-related protein Rab-1A (RAB1A) genes present in this region have been suggested to be associated with ID and/or LI pathogenesis on the basis of a few singleton cases with 2p14 microdeletions, although the effects of other deleted genes could not be ruled out. Here, we describe the clinical and molecular cytogenetic characterisation of a three-generation Japanese family comprising six individuals carrying a 144-kb microdeletion at the 2p14 locus, which disrupted two genes, ACTR2 and RAB1A, and co-segregated with ID and LI. The 5'- and 3'-deletion breakpoints were mapped within two flanking Alu repeat elements at 30-bp perfect homology, and thus suggested homologous recombination between the Alu elements as an underlying mechanism for the deletion event. Since ACTR2 is the only gene located in the minimal overlapping interval among the cases reported in the present study and those reported previously with 2p14 microdeletions, and ACTR2 exhibits strong intolerance for loss-of-function, our findings further support the notion that ACTR2, a key component involved in the branching of cytoskeletal actin networks, is probably responsible for the aetiology of LI in 2p14 microdeletion syndrome.

日本語要旨: