Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.
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Amor-Salamanca Almudena, Santana Rodríguez Alfredo, Rasoul Hazhee, Rodríguez-Palomares José F, Moldovan Oana, Hey Thomas Morris, Delgado María Gallego, Cuenca David López, de Castro Campos Daniel, Basurte-Elorz María Teresa, Macías-Ruiz Rosa, Fuentes Cañamero María Eugenia, Galvin Joseph, Bilbao Quesada Raquel, de la Higuera Romero Luis, Trujillo-Quintero Juan Pablo, García-Cruz Loida María, Cárdenas-Reyes Ivonne, Jiménez-Jáimez Juan, García-Hernández Soledad, Valverde-Gómez María, Gómez-Díaz Iria, Limeres Freire Javier, García-Pinilla José M, Gimeno-Blanes Juan R, Savattis Konstantinos, García-Pavía Pablo, Ochoa Juan Pablo
Аннотация
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.