title: An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and aTUBB3mutation.
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 inPLXND1andREV3L, 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 inTUBB3have 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ronak M
authors.identifier: 0000-0001-7217-2088
authors.initials: RM
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Lu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Fernbach
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mahshid
authors.initials: M
authors.lastname: Azamian
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: White
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Edmond
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Paysse
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Houston, Texas 77030, USA.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Pediatrics, University of Montreal, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Philippe M
authors.identifier: 0000-0001-9713-7107
authors.initials: PM
authors.lastname: Campeau
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome; D015785:Eye Diseases, Hereditary / Q000235:genetics; D005158:Facial Paralysis / Q000151:congenital / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics; D020331:Mobius Syndrome / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D015835:Ocular Motility Disorders / Q000235:genetics; D009886:Ophthalmoplegia / Q000235:genetics; D009916:Orbital Diseases / Q000235:genetics; D010375:Pedigree; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism; D000073359:Exome Sequencing
chemical_list: C498585:TUBB3 protein, human; D014404:Tubulin
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