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The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome)

Abstract

BACKGROUND

The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies.

METHODS

Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members.

RESULTS

A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2).

CONCLUSIONS

Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

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  • Authors+Show Affiliations

    ,

    Department of Medicine, Brigham and Women's Hospital, Boston, MA.

    , , , , , ,

    Source

    The New England journal of medicine 330:13 1994 Mar 31 pg 885-91

    MeSH

    Adolescent
    Adult
    Aged
    Base Sequence
    Child
    Child, Preschool
    Chromosomes, Human, Pair 12
    DNA Primers
    Female
    Genetic Linkage
    Genotype
    Hand Deformities, Congenital
    Heart Septal Defects
    Humans
    Male
    Middle Aged
    Molecular Sequence Data
    Mutation
    Pedigree
    Polymorphism, Genetic
    Syndrome

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    8114858

    Citation

    Basson, C T., et al. "The Clinical and Genetic Spectrum of the Holt-Oram Syndrome (heart-hand Syndrome)." The New England Journal of Medicine, vol. 330, no. 13, 1994, pp. 885-91.
    Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med. 1994;330(13):885-91.
    Basson, C. T., Cowley, G. S., Solomon, S. D., Weissman, B., Poznanski, A. K., Traill, T. A., ... Seidman, C. E. (1994). The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). The New England Journal of Medicine, 330(13), pp. 885-91.
    Basson CT, et al. The Clinical and Genetic Spectrum of the Holt-Oram Syndrome (heart-hand Syndrome). N Engl J Med. 1994 Mar 31;330(13):885-91. PubMed PMID: 8114858.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome) AU - Basson,C T, AU - Cowley,G S, AU - Solomon,S D, AU - Weissman,B, AU - Poznanski,A K, AU - Traill,T A, AU - Seidman,J G, AU - Seidman,C E, PY - 1994/3/31/pubmed PY - 1994/3/31/medline PY - 1994/3/31/entrez SP - 885 EP - 91 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 330 IS - 13 N2 - BACKGROUND: The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies. METHODS: Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members. RESULTS: A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2). CONCLUSIONS: Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development. SN - 0028-4793 UR - https://www.unboundmedicine.com/medline/citation/8114858/The_clinical_and_genetic_spectrum_of_the_Holt_Oram_syndrome__heart_hand_syndrome_ L2 - http://www.nejm.org/doi/full/10.1056/NEJM199403313301302?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -