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J Med Genet 40:709-713 doi:10.1136/jmg.40.9.709
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A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population

  1. S Yzer1,2,
  2. L I van den Born1,
  3. J Schuil3,
  4. H Y Kroes4,
  5. M M van Genderen3,
  6. F N Boonstra3,
  7. B van den Helm2,
  8. H G Brunner2,
  9. R K Koenekoop5,
  10. F P M Cremers2
  1. 1The Rotterdam Eye Hospital, Rotterdam, Netherlands
  2. 2Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, Netherlands
  3. 3Institute for the Visually Handicapped “Bartimeus”, Zeist, Netherlands
  4. 4Department of Medical Genetics, University Medical Centre Utrecht, Netherlands
  5. 5The McGill Ocular Genetics Laboratory, Montreal Children’s Hospital Research Institute, McGill University Montreal, Canada
  1. Correspondence to:
 Dr F P M Cremers Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands;
 f.cremers{at}antrg.umcn.nl

    Autosomal recessive retinal dystrophies cause visual impairment in approximately 1 in 4000 individuals worldwide.1 The non-syndromic forms are highly heterogeneous and can be classified into clinical subgroups, the most frequent ones being retinitis pigmentosa, cone and cone-rod dystrophies, and Leber congenital amaurosis (LCA). LCA represents the most severe phenotype with an onset of symptoms before the age of six months, visual acuity below 20/400, a searching nystagmus, sluggish pupillary reactions, and a non-detectable electroretinogram (ERG). Visual fields are usually not measurable.1 Photophobia is only occasionally reported in LCA.2 Patients with juvenile and early onset retinitis pigmentosa present with night blindness in early childhood, usually before the age of two years. They do not show searching nystagmus3 and have a relatively well preserved macular function. Central vision is often lost in the second or third decade of life.4

    The cloning of more than 20 genes allows the molecular characterisation of approximately 50% of the autosomal recessive inherited retinal dystrophy cases (http://www.sph.uth.tmc.edu/Retnet5,6 ). To establish a useful clinical prognosis for patients a well defined genotype–phenotype correlation is required.

    Although the general population in the Netherlands is relatively outbred, there are a few examples of autosomal recessive diseases caused by Dutch founder mutations. Batten disease was found to be due to identity-by-descent in a highly inbred family.7 A frequent LDL receptor mutation originating from Dutch 17th century settlers causes familial hypercholesterolaemia in South Africa and Canada.8 The RP12 locus was mapped through linkage analysis in a genetic isolate from the northwest of the Netherlands,9 which was followed by the cloning of the underlying gene, CRB1.10

    In 1959 Schappert-Kimmijser et al described an isolated Dutch population living on a former island with a relatively high frequency of LCA.11 In 1637 this …