title: OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium.
abstract: OBJECTIVE
  To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) of the retinal pigment epithelium (RPE) in two families.
  
  
  RESULTS
  Two families with autosomal-dominant PD were identified. Eight members of family 1 (five affected) were subjected to whole-genome SNP genotyping; multipoint genome-wide linkage analysis identified 7 regions of potential linkage, and genotyping four additional individuals from family 1 resulted in a maximum logarithm of odds score of 2.09 observed across four chromosomal regions. Exome sequencing of two affected family 1 members identified 15 shared non-synonymous rare coding sequence variants within the linked regions; candidate genes were prioritised and further analysed. Sanger sequencing confirmed a novel heterozygous missense variant (E79K) in orthodenticle homeobox 2 (OTX2) that segregated with the disease phenotype. Family 2 with PD (two affected) harboured the same missense variant in OTX2. A shared haplotype of 19.68 cM encompassing OTX2 was identified between affected individuals in the two families. Within the two families, all except one affected demonstrated distinct 'patterns' at the macula. In vivo structural retinal imaging showed discrete areas of RPE-photoreceptor separation at the macula in all cases. Electroretinogram testing showed generalised photoreceptor degeneration in three cases. Mild developmental anomalies were observed, including optic nerve head dysplasia (four cases), microcornea (one case) and Rathke's cleft cyst (one case); pituitary hormone levels were normal.
  
  
  CONCLUSIONS
  This is the first report implicating OTX2 to underlie PD. The retinal disease resembles conditional mice models that show slow photoreceptor degeneration secondary to loss of Otx2 function in the adult RPE.
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Forster
authors.affiliation: Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Maynes
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Paton
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Gail
authors.initials: G
authors.lastname: Billingsley
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Arfan
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Sutherland
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tom
authors.initials: T
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Westall
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D051857:Otx Transcription Factors / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology*; D016415:Sequence Alignment; D014787:Vision Tests; D055815:Young Adult
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors
keywords: Genetics; Ophthalmology