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Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction
Almudena Amor-Salamanca1, Alfredo Santana Rodríguez2,3, Hazhee Rasoul4
1Cardiology Department, Health in Code SL, A Coruña, Spain (A.A.-S., L.d.l.H.R., I.C.-R., S.G.-H., M.V.-G., I.G.-D., J.P.O.).
Insights
The TBX20 truncating variant (TBX20tv) is strongly associated with dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC). This genetic variant, found in over 70% of affected individuals, presents a non-aggressive phenotype with low major cardiovascular event rates.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Dilated cardiomyopathy (DCM) genetic diagnosis has limited yield, with less than 40% of patients identified with pathogenic variants.
- The TBX20 gene, linked to congenital heart defects, has proposed but limited evidence for association with left ventricular noncompaction (LVNC) and DCM.
Purpose of the Study:
- To investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.
- To determine the clinical characteristics and outcomes of individuals carrying the TBX20tv variant.
Main Methods:
- Next-generation sequencing of TBX20 in 7463 DCM/LVNC probands, 22,773 internal controls, and 124,098 external controls.
- Analysis of TBX20tv enrichment, cosegregation in families, and clinical data of carriers.
Main Results:
- TBX20tv was significantly enriched in DCM/LVNC cases (0.32%) compared to controls (0.004%-0.003%), with high odds ratios.
- Cosegregation analysis confirmed strong linkage (log odds score 4.53) between TBX20tv and DCM/LVNC in 21 families.
- Of 57 TBX20tv carriers, 71.9% had DCM/LVNC, with 34.1% also exhibiting congenital heart defects; follow-up showed low rates of heart failure and arrhythmias.
Conclusions:
- TBX20tv is definitively associated with DCM and LVNC, often co-occurring with congenital heart defects.
- TBX20tv-associated DCM/LVNC exhibits a non-aggressive clinical course with infrequent major adverse cardiovascular events.
- TBX20 should be included in genetic testing panels for DCM and LVNC due to its established role.
Background:
Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.
Methods:
TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.
Results:
TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.
Conclusions:
TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
