title: Lens subluxation and retinal dysfunction in a girl with homozygous VSX2 mutation.
abstract: OBJECTIVE
  To describe a unique lens subluxation phenotype in a child from a consanguineous family and to determine its genetic basis.
  
  
  METHODS
  Ophthalmologic examination (including ocular biometry and electroretinography [ERG] for the proband) and autozygosity-analysis-guided exome sequencing for the family; confirmatory candidate gene sequencing in the family and ethnically matched controls.
  
  
  RESULTS
  An otherwise healthy 3-year-old Saudi Arabian girl with poor vision since birth had smooth irides, lens subluxation, cone-rod dysfunction, and high myopia - features resembling Knobloch syndrome but differing in regard to direction of lens subluxation (superior rather than temporal) and the pattern of chorioretinal atrophy (without vitreous condensations or distinct macular atrophy). Autozygome-guided exome sequencing revealed the girl to harbor a homozygous exon 5 mutation in the ocular transcription factor gene visual homeobox 2 (VSX2) [c.773delA; p.Lys258SerfsX44] that was heterozygous in the unaffected brother and parents and absent in 100 healthy ethnically matched controls and on-line databases. Previously reported VSX2 mutations have affected the DNA-binding domains and only been associated with microphthalmia. Unlike previously reported mutations, the current VSX2 mutation is downstream to the protein's DNA binding domains.
  
  
  CONCLUSIONS
  The phenotype of this girl is unique and suggests a normal regulatory role for VSX2 in iris, zonule, and cone-rod development. For a consanguineous family with suspected recessive ocular disease but without a clear candidate gene, autozygome-guided exome analysis is a powerful technique, even when only a single patient is affected.
authors.affiliation: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital , Riyadh , Saudi Arabia .
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.forename: Jawaher
authors.initials: J
authors.lastname: Noor
authors.forename: Ahmed
authors.initials: A
authors.lastname: Salem
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D001699:Biometry; D002675:Child, Preschool; D003241:Consanguinity; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007906:Lens Subluxation / Q000235:genetics* / Q000473:pathology; D047728:Myopia, Degenerative / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C490289:VSX2 protein, human
keywords: Cone-rod; Knobloch syndrome; VSX2; ectopia lentis