TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed
Bibliographic record
Abstract
PURPOSE OF REVIEW: Mutations in the T-box transcription factor TBX5 cause Holt-Oram syndrome (HOS), an autosomal-dominant condition characterized by a familial history of congenital heart defects and preaxial radial ray upper limb defects. This review summarizes recent developments in the study of TBX5 as it relates to congenital heart disease and the pathology of HOS. RECENT FINDINGS: Currently, 37 mutations in TBX5 have been found in patients with HOS. Most of these mutations cause premature truncation of the primary TBX5 transcript, thereby presumably causing haploinsufficiency. Conversely, missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein. Although mutations are found throughout the TBX5 gene, no evidence exists to suggest that genotype affects the location of heart and limb defects or the severity of HOS manifestation. However, genetic background, and to a lesser extent, environmental and stochastic modifiers are believed to influence greatly the severity of HOS manifestation and may account for the large variation seen in the severity of defects, even among members of the same kindred. Careful clinical examination of patients who seek treatment with heart and limb malformations is necessary to avoid misdiagnosis of similar congenital conditions. With the proper examination, TBX5 mutations can be identified in more than 70% of patients with a clinical diagnosis of HOS. SUMMARY: Genetic analysis of patient populations and the biochemical characterization of the mutated proteins have provided considerable insight into the function of TBX5 in cardiac development and disease pathology. Novel discoveries await as these two paradigms merge.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".