title: The phenotypic variability of retinal dystrophies associated with mutations in CRX, with report of a novel macular dystrophy phenotype.
abstract: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone-rod homeobox (CRX) gene and to report a novel phenotype.
  
  
  
  Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives.
  
  
  
  Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-cone dystrophy (RCD), five had cone-rod dystrophy (CORD), one had cone dystrophy (COD), and six had macular dystrophy with different phenotypes observed within 5 of 11 families. The macular dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients.
  
  
  
  Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: University College London Genetics Institute, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Ophthalmology Department, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chamney
authors.affiliation: Ophthalmology Department, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.affiliation: Ophthalmology Department, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Thompson
authors.affiliation: Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom Ophthalmology Department, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein; D004247:DNA
keywords: novel mutations; phenotypes; retinal dystrophy