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A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing
  1. Jacek Majewski1,
  2. Zibo Wang1,
  3. Irma Lopez2,
  4. Sulaiman Al Humaid2,
  5. Huanan Ren1,
  6. Julie Racine2,
  7. Alex Bazinet2,
  8. Grant Mitchel1,
  9. Nancy Braverman1,
  10. Robert K Koenekoop2
  1. 1Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
  2. 2Department of Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada
  1. Correspondence to Dr Robert Koenekoop, Department of Ophthalmology, McGill University Health Centre, Montreal, QC H3H 1P3, Canada; robkoenekoop{at}

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We identified a 28-year-old cognitively normal patient with severe visual loss, absent electrical signals from the photoreceptors by electroretinogram (ERG) and nystagmus due to Leber congenital amaurosis (LCA), associated with hearing loss and Arnold–Chiari malformation. Exome sequencing detected a homozygous PEX1 mutation (p.Gly843Asp). Within a large LCA cohort, we found the mutation again in a 9-month-old baby. Peroxisome biochemical studies on both patients confirmed a peroxisome biogenesis disorder (PBD) in the Zellweger spectrum. We thus demonstrate that these patients, who had isolated LCA on presentation, actually had PBD as the cause of their LCA. Furthermore, the phenotype of the first patient was outside that of a typical Zellweger spectrum, and exome sequencing was instrumental in making this diagnosis possible.

Childhood blindness due to LCA (OMIM 204000) is a severe form of retinal photoreceptor cell degeneration and is defined by the clinical pentad of congenital visual loss, nystagmus (ocular oscillations), amaurotic pupils, retinal degeneration and absent electrical responses from both rods and cones on ERG. Mutations in 15 genes have been associated with autosomal recessive LCA, accounting for ∼70% of the patients. LCA genes are predominantly expressed in the retina, and LCA proteins participate in a variety of retinal pathways. LCA cohort studies have found that the majority of patients have an ocular phenotype only, which correlates with the predominant retinal expression of known LCA genes. However, we recently discovered three ubiquitously expressed ciliary genes that are mutated in LCA and, upon further analyses, are associated with systemic disease. We found that LCA patients with mutations in CEP290 or LCA5 develop olfactory defects. We then identified NPHP5 mutations causing LCA, prompted by protein homology and binding to CEP290, and found that they may result in kidney failure.1–4 These findings indicate the necessity for a paradigm shift in our understanding …

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  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The Research Institute of McGill University Health Centre.

  • Provenance and peer review Not commissioned; externally peer reviewed.