[Holt-Oram syndrome: family affected without TBX5 mutation and without phenotype manifestations in a probable mutation carrier].

Holt-Oram syndrome (HOS) is a disorder characterized by skeletal abnormalities in the upper limbs accompanied by cardiovascular defects. The diagnosis of HOS is based on these abnormalities and defects, both in the individual or in the parents, and is indicative of congenital transmission. All those affected by this syndrome have upper limb skeletal abnormalities, which preferentially affect the thumbs. Of those diagnosed with this syndrome, 75% have cardiovascular defects, atrial septal defect being the most frequent. The lack of correlation between the severity of the skeletal and cardiac lesions is well known, as well as the heterogeneity of the syndrome in the affected relatives. The causative gene TBX5, located on chromosome 12, was discovered in 1997. This has an autosomal dominant transmission with 100% penetrance. The location and type of mutation in TBX5 are not predictive of phenotypic expression. The probability of finding the mutation in the TBX5 gene is 74% in patients who fulfill the clinical criteria for HOS. We present the clinical case of a 14-year-old girl with hypoplastic thumbs who had been diagnosed with an ostium secundum atrial septal defect (Fig. 1). A maternal uncle has a similar thumb malformation. All those who were candidate for inheriting the mutation (Fig. 2) underwent Doppler echocardiography and electrocardiography study with no findings of note. As the mother was considered the probable transmitter of the genetic disorder, despite having no bone or cardiac defects, an x-ray of her hands was performed which ruled out any subclinical bone malformation. After obtaining informed consent, genomic DNA from the patient was extracted and purified, followed by PCR amplification specific to all the exons and intron flanking regions of the TBX5 gene. Finally, direct sequencing of all the purified double-stranded PCR fragments was performed. No variations in the nucleotide sequence were found such that HOS could be confirmed. In 2006, Borozdin et al. detected deletions in one or several exons or even of the entire TBX5 gene in around 2% of individuals with HOS who did not present mutations identified via sequencing. The study of this family was completed by MLPA (Multiplex