Multigenic involvement of the semaphorin-plexin pathway in Moebius syndrome by a germline chromothriptic rearrangement. Chromothripsis

BackgroundMoebius syndrome (MBS) is a congenital disorder mostly caused by unilateral or bilateral paralysis of the facial (cranial nerve VII) and abducens (cranial nerve VI) nerves. Both genetic defects and environmental toxic factors leading to abnormal brainstem development are proposed to be involved in the aetiology of MBS. Recently, mutations in PLXND1 and REV3L were confirmed to cause MBS. Although other candidate genes have been proposed, sequencing of MBS cohorts have not detected any causative mutations in them.Methods Here, we applied next generation mate-pair sequencing to map a complex chromosomal rearrangement (CCR) 46,XY,t(7;8;11;13) in a previously reported patient with MBS, and confirmed 39 out of 41 breakpoint-junctions by Sanger sequencing. Results The molecular mapping revealed 41 clustered breakpoints, involving chromosomes 7, 8, 11 and 13, resulting in heavy intra- and interchromosomal rearrangements with typical hallmarks of chromothripsis. Among 12 truncated protein-coding genes, SEMA3A and SEMA3D are attractive candidates for the MBS features, as they encode class 3 semaphorins, where SEMA3A is known to bind to the MBS-associated PLXND1. Intruigingly, the CCR also truncated PIK3CG, which in silico interacts with the other known MBS-gene REV3L, and with the SEMA3A/PLXND1 complex via the vascular endothelial growth factor FLT1. Conclusion The simultaneous truncation of several interactors of the known MBS-genes by a single CCR suggests that the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders.