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Novel SOX2 mutations and genotype–phenotype correlation in anophthalmia and microphthalmia

Authors

  • Adele Schneider,

    1. Albert Einstein Medical Center, Department of Pediatrics Division of Genetics, Milwaukee, Wisconsin
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  • Tanya Bardakjian,

    1. Albert Einstein Medical Center, Department of Pediatrics Division of Genetics, Milwaukee, Wisconsin
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  • Linda M. Reis,

    1. Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin
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  • Rebecca C. Tyler,

    1. Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin
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  • Elena V. Semina

    Corresponding author
    1. Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin
    2. Department of Cell Biology, Neurobiology and Anatomy at the Medical College of Wisconsin, Milwaukee, Wisconsin
    • C3520, Translational and Biomedical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509.
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  • How to Cite this Article: Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV. 2009. Novel SOX2 mutations and genotype–phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet Part A 149A:2706–2715.

Abstract

SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and identified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families. © 2009 Wiley-Liss, Inc.

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