OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype

Authors

  • KF Schilter,

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

    1. Department of Pediatrics, Division of Genetics, Albert Einstein Medical Center, Philadelphia, PA, USA
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  • T Bardakjian,

    1. Department of Pediatrics, Division of Genetics, Albert Einstein Medical Center, Philadelphia, PA, USA
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  • J-F Soucy,

    1. Medical Genetics Division, CHU Sainte-Justine, 3175 Côte-Sainte-Catherine, Montréal, Québec, Canada
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  • RC Tyler,

    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA
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  • LM Reis,

    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA
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  • EV Semina

    Corresponding author
    1. Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA
    2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
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Elena V Semina, C3520, Translational and Biomedical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA.
Tel.: +1 414 955 4996;
fax: +1 414 955 6329;
e-mail: esemina@mcw.edu

Abstract

Schilter KF, Schneider A, Bardakjian T, Soucy J-F, Tyler RC, Reis LM, Semina EV. OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype.

The OTX2 homeobox-containing transcription factor gene was shown to play a key role in the development of head structures in vertebrates. In humans, OTX2 mutations result in anophthalmia/microphthalmia (A/M) often associated with systemic anomalies. We screened 52 unrelated individuals affected with A/M and identified disease-causing variants in four families (8%), a higher frequency than previously reported. All four mutations are predicted to result in truncation of normal OTX2 protein sequence, consistent with previously reported mechanisms; three changes occurred de novo and one mutation was inherited from an affected parent. Four of the five OTX2-positive patients in our study displayed additional systemic findings, including two novel features, Wolf–Parkinson–White syndrome and an anteriorly placed anus. Analysis of the phenotypic features of OTX2-positive A/M patients in this study and those previously reported suggests the presence of pituitary anomalies and lack of genitourinary and gastrointestinal manifestations as potential distinguishing characteristics from SOX2 anophthalmia syndrome. Interestingly, pituitary anomalies seem to be more strongly associated with mutations that occur in the second half of OTX2, after the homeodomain and SGQFTP motif. OTX2 patients also show a high rate of inherited mutations (35%), often from mildly or unaffected parents, emphasizing the importance of careful parental examination/testing.

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