Submission Details

The T-box 5 (TBX5) gene is located on chromosome 12 at 12q24.21 and encodes a transcriptional regulator that is involved in cardiac development and limb pattern formation Mutations in TBX5 were first reported in relation to autosomal dominant Holt-Oram syndrome (HOS), a developmental disorder affecting the heart and upper limb, in 1997 (Basson et al., 1997, PMID: 8988165; Li et al., 1997, PMID: 8988164). At least 120 unique variants (missense, nonsense, frameshift, small deletions) have been reported in humans, the majority which are de novo. The upper-limb malformations associated with HOS are fully penetrant, whereas the congenital heart malformations associated with the disease may be less so. In some cases, the cardiac phenotype may be recognized prior to limb anomalies, as some upper limb malformations have a very mild presentation. In patients with mild upper limb anomalies, conduction defects may present well into adulthood with reverse phenotyping prompting skeletal assessment (PMID 29755943). Cardiac conduction defects that are associated with HOS may occur in the presence or absence of structural heart defects. While septal defects are the most common structural disease association, cardiac phenotypes including dilated and non-compaction cardiomyopathies, and complex congenital heart diseases including dextrocardia, tetralogy of fallot, and double outlet right ventricle have been reported (PMIDs 3055242, 25344219, 32449309).

Evidence supporting this gene-disease relationship includes case-level and experimental data.The mechanism for TBX5 is haploinsufficiency (Basson et al., 1999, PMID:10077612; Gruenauer-Kloevekorn et al., 2003, PMID 12818525; Baban et al., 2014, PMID 24664498). This gene-disease association is supported by animal models, protein interaction studies. Functional alterations were also shown in non-patient cells harbouring missense variants in TBX5 in different affected individuals. In summary, TBX5 is definitively associated with Holt-Oram syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 26Jan2021 (SOP Version 8). The summary was updated by the ClinGen Hereditary Cardiovascular Disease GCEP after meeting on March 25, 2025.