TBX20 – Dilated Cardiomyopathy

1. Inheritance and Clinical Validity

TBX20 encodes a T-box transcription factor essential for cardiac morphogenesis and adult cardiomyocyte homeostasis. Heterozygous TBX20 variants have been implicated in autosomal dominant dilated cardiomyopathy (DCM). Based on two independent loss-of-function pedigrees and additional promoter variants in DCM cohorts, with concordant functional data, the gene–disease association is classified as Moderate.

2. Genetic Evidence

A novel nonsense variant, c.428G>T (p.Glu143Ter), was identified in a patient with adult-onset DCM and co-segregated with DCM (and atrial septal defect) in all affected relatives; it was absent in 800 controls (PMID:27510170). A missense variant, c.766T>A (p.Phe256Ile), co-segregated with familial DCM with complete penetrance and was absent in 600 controls (PMID:26118961). Promoter sequencing in 107 DCM patients revealed five novel or rare noncoding variants absent in 210 controls, supporting recurrent TBX20 involvement in DCM (PMID:38284443).

3. Variant Spectrum

Variants span truncating changes (nonsense, frameshift) and missense substitutions (e.g., c.766T>A (p.Phe256Ile)), as well as regulatory promoter alterations (e.g., g.4275G>T) that modulate gene expression.

4. Functional Evidence

Dual-luciferase assays demonstrate that truncating TBX20 proteins lack transcriptional activity and disrupt synergistic activation with NKX2-5 and GATA4 (PMID:27510170; PMID:26118961). Adult cardiomyocyte–specific Tbx20 ablation in mice leads to rapid-onset DCM and arrhythmias, mirroring human disease (PMID:22080862). Promoter variants significantly alter TBX20 expression and transcription factor binding in vitro (PMID:38284443).

5. Conflicting Evidence

No studies have robustly refuted the TBX20–DCM link or identified these specific coding or promoter variants as benign in large control cohorts.

6. Conclusion

Heterozygous TBX20 variants cause autosomal dominant DCM through haploinsufficiency, supported by segregation in two families, loss-of-function assays, and an adult cardiomyocyte knockout model. TBX20 should be included in DCM genetic testing panels to guide diagnosis and familial risk assessment.

References

• Journal of clinical investigation • 2011 • Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function PMID:22080862
• Molecular medicine reports • 2016 • A novel TBX20 loss-of-function mutation contributes to adult-onset dilated cardiomyopathy or congenital atrial septal defect PMID:27510170
• Clinical chemistry and laboratory medicine • 2016 • TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy PMID:26118961
• Molecular genetics & genomic medicine • 2024 • Genetic and functional variants of the TBX20 gene promoter in dilated cardiomyopathy PMID:38284443

Evidence Based Scoring (AI generated)