• Open Access

Deficiency of the Cyclin-Dependent Kinase Inhibitor, CDKN1B, Results in Overgrowth and Neurodevelopmental Delay

Authors

  • William Grey,

    1. Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London, United Kingdom
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  • Louise Izatt,

    1. Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
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  • Wafa Sahraoui,

    1. Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London, United Kingdom
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  • Yiu-Ming Ng,

    1. Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London, United Kingdom
    2. Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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  • Caroline Ogilvie,

    1. Cytogenetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
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  • Anthony Hulse,

    1. Department of Paediatrics, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
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  • Eric Tse,

    1. Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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  • Roman Holic,

    1. Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Ivanka pri Dunaji, Slovakia
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  • Veronica Yu

    Corresponding author
    1. Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
    • Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London, United Kingdom
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  • Communicated by Hamish S. Scott

  • Contract grant sponsors: National Institutes of Health Research Biomedical Research Centre at Guy's and St Thomas’ NHS Foundation Trust; King's College London; the Wellcome Trust; Academy of Medical Sciences; British Heart Foundation; Generation Trust PhD Studentship; Joint KCL/HKU PhD Studentship.

Correspondence to: Veronica Yu, Department of Medical & Molecular Genetics, King's College London School of Medicine, Level 8, Tower Wing Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. E-mail: veronica.yu@kcl.ac.uk

ABSTRACT

Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay.

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