THE CLINICAL AND GENETIC SPECTRUM OF THE HOLT-ORAM SYNDROME (HEART-HAND SYNDROME)

Background. The Holt-Gram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanie d by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt -Gram syndrome gene, we performed clinical and genetic studies. Method s. Two large families with the Holt-Gram syndrome were evaluated by ra diography of the hands, electrocardiography, and transthoracic echocar diography. Genetic-linkage analyses were performed with polymorphic DN A loci dispersed throughout the genome to identify a locus that was in herited with the Holt-Gram syndrome in family members. Results. A tota l of 19 members of Family A had Holt-Oram syndrome with mild-to-modera te skeletal deformities, including triphalangeal thumbs and carpal-bon e dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septa l defects or atrioventricular-canal defects. Eighteen members of a sec ond kindred (Family B) had Holt-Gram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected mem bers had no cardiac defects; six had only atrial septal defects. Genet ic analyses demonstrated linkage of the disease in each family to poly morphic 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-Gram syndrome is present on the long arm of ch romosome 12 (12q2). Conclusions. Mutations in a gene on chromosome 12q 2 can produce a wide range of disease phenotypes characteristic of the Holt-Gram syndrome. This gene has an important role in both skeletal and cardiac development.