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Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia

Authors

  • B. Deml,

    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
    2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
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  • L.M. Reis,

    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
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  • M. Maheshwari,

    1. Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA
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  • C. Griffis,

    1. Division of Genetics, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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  • D. Bick,

    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
    2. Division of Genetics, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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  • E.V. Semina

    Corresponding author
    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
    2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
    • Correspondence author: Elena V. Semina, Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

      Tel.: +414 955 4996;

      fax: +414 955 6329;

      email: esemina@mcw.edu

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  • The authors declare that they have no conflict of interest.

Abstract

Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern.

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