An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a TUBB3 mutation

Cold Spring Harb Mol Case Stud. 2017 Mar;3(2):a000984. doi: 10.1101/mcs.a000984.

Abstract

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in PLXND1 and REV3L, we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (TUBB3), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in TUBB3 have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

Keywords: aplasia/hypoplasia involving bones of the lower limbs; aplasia/hypoplasia involving bones of the upper limbs; aplasia/hypoplasia of the extremities; congenital extraocular muscle anomaly; congenital fibrosis of extraocular muscles.

Publication types

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

MeSH terms

  • Child
  • Child, Preschool
  • Cohort Studies
  • Exome
  • Eye Diseases, Hereditary / genetics
  • Facial Paralysis / congenital
  • Facial Paralysis / genetics
  • Female
  • Humans
  • Infant
  • Male
  • Malformations of Cortical Development / genetics
  • Mobius Syndrome / genetics*
  • Muscular Diseases / genetics
  • Mutation
  • Ocular Motility Disorders / genetics
  • Ophthalmoplegia / genetics
  • Orbital Diseases / genetics
  • Pedigree
  • Tubulin / genetics*
  • Tubulin / metabolism
  • Whole Exome Sequencing

Substances

  • TUBB3 protein, human
  • Tubulin