[Holt-Oram syndrome: characterization of a novel mutation]

Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype.

The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome.

Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out.

Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome.