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Abstract

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

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Author information

Author notes

    • Craig T. Basson1
    •  & David R. Bachinsky

    C.T.B.&D.R.B. contributed equally to this work.

Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • Craig T. Basson1
    •  & Christine E. Seidman
  2. Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • David R. Bachinsky
    • , Robert C. Lin
    • , Tatjana Levi
    • , Jacob A. Elkins
    • , Johann Soults
    • , David Grayzel
    • , Elena Kroumpouzou
    •  & Seidman J.G
  3. Cardiology Division, Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland 21205, USA.

    • Thomas A. Traill
  4. Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx New York 10461, USA.

    • Janine Leblanc-Straceski
    • , Beatrice Renault
    •  & Raju Kucherlapati
  5. Current address: Department of Biology, Merrimack College, North Andover, Massachusetts 01845, USA.

    • Janine Leblanc-Straceski
  6. Howard Hughes Medical Institute, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • Christine E. Seidman
  7. Correspondence should be addressed to C.T.B.

    • Craig T. Basson1

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DOI

https://doi.org/10.1038/ng0197-30

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