Holt-Oram syndrome and differential diagnosis [42 genes]

Holt-Oram syndrome is an autosomal dominant disorder characterized by anomalies in the upper extremities and shoulder girdle associated with a congenital heart lesion. The typical combination is considered to be a triphalangeal thumb with an atrial septal defect, although there is heterogeneity in the severity of cardiac and skeletal lesions (OMIM: 142900).

Holt-Oram syndrome: 1 / 100,000 live births (ORPHA:392).

In Holt-Oram syndrome, the benefit of the genetic study is confirmation of the diagnosis, family genetic counseling with the establishment of secondary prevention measures based on the use of anticoagulants or antibiotic prophylaxis of bacterial endocarditis.

Service is particularly indicated when there are clinical signs of suspicion, such as malformations of the upper extremity with a septation or cardiac conduction defect. Otherwise, it is recommended to order a whole exome directed by the patient’s phenotype.

70% of patients with a clinical diagnosis of the disease carry pathogenic variants in the nucleotide sequence, with CNVs being very rare. The percentage of patients without an identifiable molecular cause reaches 30%. Therefore, by exome sequencing, it is possible to achieve a diagnostic yield of approximately 70%.