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Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants
Clémence Vanlerberghe1,2, Anne-Sophie Jourdain3,4, Jamal Ghoumid5,3
1CHU Lille, Clinique de Génétique, 59000, Lille, France. clemence.vanlerberghe@chru-lille.fr.
Insights
Holt-Oram syndrome (HOS) is a genetic disorder affecting heart and limb development. This study identified TBX5 variants in 78 patients, improving understanding of HOS diagnosis and genotype-phenotype correlations.
Area of Science:
- Genetics and Molecular Biology
- Cardiology
- Developmental Biology
Background:
- Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by congenital heart defects (CHD) and radial limb abnormalities.
- Diagnosis of HOS is complicated by variable expressivity and overlap with other genetic syndromes.
- TBX5 gene variants are the known cause of HOS.
Purpose of the Study:
- To investigate the spectrum of TBX5 variants in a large cohort of patients suspected of having HOS.
- To correlate genotype with phenotype in HOS patients.
- To identify key features aiding in HOS diagnosis and molecular delineation.
Main Methods:
- Retrospective review of 212 patients referred for suspected HOS between 2002 and 2014.
- TBX5 gene screening was performed on all patients.
- Detailed clinical and molecular data were analyzed.
Main Results:
- TBX5 variants were identified in 78 patients, the largest molecular series reported to date.
- Congenital heart defect (CHD) was present in 91% of patients with TBX5 variants, with atrial septal defects being most common (61.5%).
- Key features associated with HOS include septal CHD, bilateral/asymmetric radial defects, and shoulder/elbow mobility issues. 21 patients had overlapping conditions.
Conclusions:
- TBX5 variant screening is crucial for diagnosing HOS.
- Specific phenotypic features aid in identifying HOS and differentiating it from similar conditions.
- Further strategies are needed to refine molecular diagnosis in complex HOS cases.
Abstract:
Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.
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