Multigenic truncation of the semaphorin–plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome

Lusine Nazaryan-Petersen, Inês R. Oliveira, Mana M. Mehrjouy, Juan M.M. Mendez, Mads Bak, Merete Bugge, Vera M. Kalscheuer, Iben Bache, Dustin C. Hancks, Niels Tommerup

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Moebius syndrome (MBS) is a congenital disorder caused by paralysis of the facial and abducens nerves. Although a number of candidate genes have been suspected, so far only mutations in PLXND1 and REV3L are confirmed to cause MBS. Here, we fine mapped the breakpoints of a complex chromosomal rearrangement (CCR) 46,XY,t(7;8;11;13) in a patient with MBS, which revealed 41 clustered breakpoints with typical hallmarks of chromothripsis. Among 12 truncated protein-coding genes, SEMA3A is known to bind to the MBS-associated PLXND1. Intriguingly, the CCR also truncated PIK3CG, which in silico interacts with REVL3 encoded by the other known MBS-gene REV3L, and with the SEMA3A/PLXND1 complex via FLT1. Additional studies of other complex rearrangements may reveal whether the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders.

Original languageEnglish (US)
Pages (from-to)1057-1062
Number of pages6
JournalHuman mutation
Volume40
Issue number8
DOIs
StatePublished - Jan 1 2019

Keywords

  • Moebius syndrome
  • PIK3CG
  • SEMA3A
  • SEMA3D
  • chromothripsis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Nazaryan-Petersen, L., Oliveira, I. R., Mehrjouy, M. M., Mendez, J. M. M., Bak, M., Bugge, M., Kalscheuer, V. M., Bache, I., Hancks, D. C., & Tommerup, N. (2019). Multigenic truncation of the semaphorin–plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome. Human mutation, 40(8), 1057-1062. https://doi.org/10.1002/humu.23775