TY - JOUR
T1 - Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction
AU - Amor-Salamanca, Almudena
AU - Santana Rodríguez, Alfredo
AU - Rasoul, Hazhee
AU - Rodríguez-Palomares, José F.
AU - Moldovan, Oana
AU - Hey, Thomas Morris
AU - Gallego-Delgado, María
AU - Cuenca, David López
AU - de Castro Campos, Daniel
AU - Basurte-Elorz, María Teresa
AU - Macías-Ruiz, Rosa
AU - Fuentes Cañamero, María Eugenia
AU - Galvin, Joseph
AU - Bilbao Quesada, Raquel
AU - de la Higuera Romero, Luis
AU - Trujillo-Quintero, Juan Pablo
AU - García-Cruz, Loida María
AU - Cárdenas-Reyes, Ivonne
AU - Jiménez-Jáimez, Juan
AU - García-Hernández, Soledad
AU - Valverde-Gómez, María
AU - Gómez-Díaz, Iria
AU - Limeres Freire, Javier
AU - García-Pinilla, José Manuel
AU - Gimeno-Blanes, Juan R.
AU - Savattis, Konstantinos
AU - García-Pavía, Pablo
AU - Ochoa, Juan Pablo
N1 - Publisher Copyright:
© 2024 The Authors.
PY - 2024/4/1
Y1 - 2024/4/1
N2 - 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.
AB - 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.
KW - Cardiomyopathies
KW - Cardiomyopathy, dilated
KW - Heart defects, congenital
KW - Heart ventricles
KW - High-throughput nucleotide sequencing
KW - Human genetics
KW - Transcription factors
UR - http://www.scopus.com/inward/record.url?scp=85190724018&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/ecbdfae3-0adb-314e-b5d7-1c6d3b913686/
U2 - 10.1161/CIRCGEN.123.004404
DO - 10.1161/CIRCGEN.123.004404
M3 - Article
C2 - 38353104
SN - 1942-325X
VL - 17
SP - E004404
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -