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

Hum Mutat. 2019 Aug;40(8):1057-1062. doi: 10.1002/humu.23775. Epub 2019 May 14.

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.

Keywords: Moebius syndrome; PIK3CG; SEMA3A; SEMA3D; chromothripsis.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Breakpoints
  • Chromothripsis*
  • Fatal Outcome
  • Gene Rearrangement
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Mobius Syndrome / genetics*
  • Semaphorin-3A / genetics
  • Semaphorins / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • PLXND1 protein, human
  • SEMA3A protein, human
  • Semaphorin-3A
  • Semaphorins