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OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium
  1. Ajoy Vincent1,2,3,
  2. Nicole Forster2,
  3. Jason T Maynes4,5,
  4. Tara A Paton2,6,
  5. Gail Billingsley2,
  6. Nicole M Roslin2,6,
  7. Arfan Ali2,
  8. Joanne Sutherland1,
  9. Tom Wright1,
  10. Carol A Westall1,3,
  11. Andrew D Paterson2,3,6,
  12. Christian R Marshall2,6,
  13. FORGE Canada Consortium,
  14. Elise Héon1,2,3
  1. 1Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3University of Toronto, Toronto, Ontario, Canada
  4. 4Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  5. 5Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  1. Correspondence to Dr Ajoy Vincent, Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, 525 University Avenue, Suite 800, Toronto, Ontario, Canada M5G 1X8; ajoy.vincent{at}, ajoyvincent{at}


Purpose To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) of the retinal pigment epithelium (RPE) in two families.

Methods and 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.

  • Ophthalmology
  • Genetics

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