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Irma Lopez-Solache, Zibo Wang, Ren Huanan, Leah Wood, Grant Mitchel, Racine Julie, Nancy Braverman, Jacek Majewski, Robert K. Koenekoop; A New Ocular Phenotype Associated With An Unexpected, But Known Systemic Disorder And Mutation: Novel Use Of Genomic Diagnostics And Exome Sequencing. Invest. Ophthalmol. Vis. Sci. 2011;52(14):63.
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To identify the causal gene in a Quebec LCA patient with 25 significant homozygous regions.
We excluded common mutations in LCA genes (APEX). We then performed whole genome SNP genotyping (660K). By exome capture (Agilent SureSelect Human All Exon Kit) we sequenced 180,000 exons and re-phenotyped the patient.
The patient is a highly intelligent and successful pharmacist with 20/400 acuities, nystagmus, non-detectable ERGs, retinal dystrophy, sensorineural hearing loss, and Arnold Chiari I malformation with related hydrosyringomyelia. We identified the well known homozygous Glycine-843-Aspartic-acid (G843D) missense mutation in PEX1, which encodes peroxin-1, a peroxisome membrane-associated protein involved in protein transport. PEX1 mutations are a well established cause of Zellweger Spectrum Disorders, characterized by mental retardation, multisystem failure and childhood death. Peroxisome metabolic functions in blood and urine were mildly abnormal, consistent with her mild clinical presentation. We analyzed 100 highly selected LCA cases and identified the G843D mutation again, in a 6 month old LCA baby that was systemically healthy. A year later this child developed life threatening liver failure and received the diagnosis of a severe peroxisome biogenesis disorder.
We report 2 LCA patients with PEX1 mutations. In one, the systemic features were so mild, that they did not reach clinical significance or were thought to be insignificant compared to the blindness. In the second LCA patient, the initial presentation of disease was blindness, followed by the development of systemic disease a year later. PEX1 mutations, specifically G843D should be tested in all newborns with LCA, to predict the development of systemic disease later in life. NGS and exome capture combined with homozygosity mapping provides an excellent, efficient diagnostic method to find mutations. Unexpected phenotypes due to known mutations can be identified by NGS.
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