New article on a causative gene for dilated cardiomyopathy: truncating variants in TBX20 are associated with its development

  • A new collaborative study led by Health in Code’s Cardiology Team with the participation of more than 20 national and international centers has been published in the journal Circulation: Genomic and Precision Medicine.
  • The results demonstrate the association of TBX20 with the development of dilated/noncompaction cardiomyopathy; therefore, this gene should be included in the list of genes considered causative of DCM/NCCM in humans.



Madrid, March, 19, 2024.

Thanks to the use of NGS techniques, our knowledge about genetics is increasing, but it is often scattered across different works and studies. To demonstrate the association between certain genes or variants and certain diseases, this information needs to be analyzed jointly.


Hence the importance of the new collaborative study led by Health in Code’s Cardiology Team, with Almudena Amor, MD, PhD as first author and led by Juan Pablo Ochoa, MD, PhD: “Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction”. This article, published in Circulation: Genomic and Precision Medicine, has brought together 20 centers to assess the association of certain variants in the TBX20 gene with the development of dilated/noncompaction cardiomyopathy.


Dr. Almudena Amor Salamanca, Scientific Head of Health in Code’s Cardiology Team and first author of the paper, delves into some of aspects of the study:



What has the history of the TBX20 gene been like? What do guidelines say about it so far?


“Functional studies and animal models for the TBX20 gene were already available, and they had associated pathogenic variants in this gene with the development of congenital heart disease. Some studies had also suggested its association with dilated and noncompaction cardiomyopathy after identifying some variants in small families with no clear cosegregation.


For these reasons, the ClinGen Consortium (dedicated to gene curation and association with different phenotypes by experts) considers TBX20 to be a gene with limited evidence for its association with dilated cardiomyopathy. This is its description in the latest European Society of Cardiology Guidelines for the management of cardiomyopathies (published last summer): a gene with limited evidence for its association with the development of dilated cardiomyopathy and with sporadic noncompaction cases described.”



Before this new study, in how many families had segregation with the phenotype been demonstrated?


“The first study that associated TBX20 with cardiomyopathy in humans was published by Kirk et al. in 2007. This group identified two variants (p.Ile152Met and p.Glu195*) in TBX20 in patients with congenital heart disease and dilated cardiomyopathy. Variant p.Glu195* cosegregated in six members of a family with a mixed phenotype including septal defects, mitral valve involvement, and cardiomyopathy. Later, Zhao et al. described variant p.Phe256Ile in a family with four carriers affected with dilated cardiomyopathy (one of them also showing septal defects). Since then, most variants (most of them missense) have been identified in cohorts of dilated or noncompaction cardiomyopathy patients or in case reports (with little or no information available about familial cosegregation).”



What is the significance of this new study led by Health in Code?


“This new work demonstrates that truncating variants in the TBX20 gene (TBX20tv) are associated with the development of dilated/noncompaction cardiomyopathy (DCM/NCCM) by analyzing multiple families, thus proving segregation with the phenotype.

The clinical progression of the disease is not particularly aggressive, and only a small proportion of patients develop ventricular dysfunction or suffer ventricular arrhythmias.


With these results, it is expected for the evidence for the association between TBX20 and dilated cardiomyopathy to be considered definitive and for the gene to be included in genetic testing for all dilated cardiomyopathy patients, particularly in those with concomitant hypertrabeculation or congenital heart defects.”



What are truncating variants? Why are they important in this gene and for this specific disease?


“Truncating variants include all those associated with the generation of shortened proteins or with the absence of protein synthesis dependent on that copy of the gene. These include nonsense, frameshift, and splicing-affecting variants. The proteins that result from these changes may not perform their function correctly. If the affected gene does not tolerate the loss of one of the two alleles, this situation leads to haploinsufficiency, a known disease mechanism in some genes. Previous studies had shown that TBX20 does not tolerate haploinsufficiency. What this study has shown is that this loss of function in the human heart leads to the development of dilated cardiomyopathy, often associated with noncompaction and/or congenital defects.”



What does cosegregation mean?


“Segregation (or cosegregation) analysis between a given variant and phenotype is one of the criteria assessed to determine whether a variant may be pathogenic. If all individuals affected with a disease within a family carry the variant and all non-affected individuals are non-carriers, this variant is said to segregate with the phenotype in this family. This is not enough to determine whether this variant is causative, but if this is observed in many families from different origins, it is a very important piece of information.


Conversely, if the variant does not cosegregate (some family members affected with the disease do not carry the variant), this information is also relevant to rule out the involvement of said variant in the phenotype. Demonstrating cosegregation is sometimes difficult, as all family members (both affected and not affected) need to be tested, and families are sometimes geographically scattered or do not have many members.”



In your opinion, how important are collaborative studies in genetics?


“Studies like this one, in which multiple centers contribute clinical and genetic information to be analyzed jointly, allow establishing definitive associations, therefore advancing genetic knowledge. In Spain, collaboration among centers is thankfully widespread, and these types of studies are common in the field of familial heart disease.”



Does Health in Code’s dilated cardiomyopathy panel include the TBX20 gene?

“The TBX20 gene has been included in Health in Code’s dilated cardiomyopathy panel since 2014, not as a priority or disease-related gene, but due to associations described in functional studies and animal models. We routinely review the evidence published for the different genes and, according to said evidence, we classify them into priority or non-priority genes for that specific phenotype. Thus, if there are data supporting the association of a gene with a specific disease, we can detect and study that gene. As of now, we have sequenced this gene in more than 37,000 probands tested in our center thanks to our many years of work. Integrating research into daily clinical practice is essential for any cutting-edge center; only then can science advance.”




Scientific article: Amor-Salamanca A, et al. Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction. Circ Genom Precis Med. 2024 Feb 14:e004404. doi: