title: Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy.
abstract: OBJECTIVE
  To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD).
  
  
  METHODS
  We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT.
  
  
  RESULTS
  The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas.
  
  
  CONCLUSIONS
  A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution.
authors.affiliation: Université Paris-Descartes, Faculté de Médecine Paris Descartes-site Necker, CERTO, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lacassagne
authors.forename: Aurore
authors.initials: A
authors.lastname: Dhuez
authors.forename: Florence
authors.initials: F
authors.lastname: Rigaudière
authors.forename: Anouk
authors.initials: A
authors.lastname: Dansault
authors.forename: Christelle
authors.initials: C
authors.lastname: Vêtu
authors.forename: Karine
authors.initials: K
authors.lastname: Bigot
authors.forename: Véronique
authors.initials: V
authors.lastname: Vieira
authors.forename: Bernard
authors.initials: B
authors.lastname: Puech
authors.forename: Sabine
authors.initials: S
authors.lastname: Defoort-Dhellemmes
authors.forename: Marc
authors.initials: M
authors.lastname: Abitbol
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000075002:Bestrophins; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D004585:Electrooculography / Q000379:methods; D004596:Electroretinography / Q000379:methods; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000473:pathology; D017422:Sequence Analysis, DNA; D041623:Tomography, Optical Coherence / Q000379:methods; D057826:Vitelliform Macular Dystrophy / Q000235:genetics*
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins