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Previous Volume 330:885-891 March 31, 1994 Number 13 Next

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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 10¹⁶:1 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.

Source Information

From the Cardiovascular Division, Department of Medicine (C.T.B., S.D.S., C.E.S.), and the Department of Radiology (B.W.), Brigham and Women's Hospital, Boston; Harvard Medical School, Boston (C.T.B., S.D.S., C.E.S.); the Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston (G.S.C., J.G.S.); the Department of Radiology, Children's Memorial Hospital, Chicago (A.K.P.); and the Cardiovascular Division, Department of Medicine, Johns Hopkins Hospital, Baltimore (T.A.T.).

Address reprint requests to Dr. Christine Seidman at the Department of Genetics, Harvard Medical School, Alpert Bldg., Rm. 533, 200 Longwood Ave., Boston, MA 02115.

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