Impact of genotype-phenotype associations on prognosis in dilated cardiomyopathy
A single genetic variant can be found in up to 40% of patients with DCM. Because different genes can lead to different heart problems (for example an irregular heart beat or problems of the pumping function), understanding these gene-specific patterns is important for predicting risks and choosing the best treatment for the individual patient. In this study, researchers looked at 534 people with DCM who all had a genetic variant. This group of patients was analyzed in two different ways. First, people were grouped based on the exact genetic mutation (a so-called “genotype-first” approach). Second, they created groups based only on how the disease appeared clinically in terms of symptoms (things like heart function and the presence of arrhythmias) without considering the information on genetics (a so-called “phenotype-first” approach). They then compared these two approaches to see how well the genetic information relates to the clinical features and how accurate each approach could predict the prognosis of a patient. The genotype-first approach revealed clear patterns. For example, some genes (like FLNC, LMNA, DSP, and PLN) were strongly linked to problems with the heart rhythm, while others (like BAG3, TNNT2, DMD, and TTN) were associated with enlarged hearts and reduced pumping ability with relatively few heart rhythm problems. The phenotype-first approach revealed four main patient groups, 1: young patients, moderately reduced heart function; 2: moderately reduced heart function with rhythm disturbances, 3: poor heart function and 4: poor heart function and rhythm disturbances. Interestingly, the clinical groups did not line up well with genetic information. In other words, people with similar symptoms could have very different underlying genetic causes. When looking at the prognosis, certain genes (especially LMNA, FLNC, and BAG3) were associated with the highest risk of severe events. The phenotype-first groups also identified high-risk groups, but overall, the gene-based approach did a better job predicting long-term prognosis. This shows that although it is very common that doctors provide advice based only on the clinical information, knowing the underlying genetic problem can provide more important information.
In summary, people with genetic DCM can look very different from one another clinically, even if they share the same gene defect. However, the genetic variant is still the strongest predictor of how the disease will progress. Therefore, the study supports broad genetic testing for all patients with DCM and encourages more gene-specific guidance in the clinical care for patients.
Paper: Stroeks SLVM, Wang P, Merlo M, Muller S, Paldino A, Mora-Ayestaran N, Jason M, Ferro MD, Loca CP, Dominguez F, Gonzalez-Lopez E, van den Wijngaard A, Venner MFGHM, Sikking M, Minten M, Nihant B, Beelen N, Graw S, Medo K, de Koning B, Taylor M, van Tintelen JP, Mestroni L, Sinagra G, Te Riele ASJM, Garcia-Pavia P, Heymans S, Verdonschot JAJ. Impact of genotype-phenotype associations on prognosis in dilated cardiomyopathy.
Eur J Heart Fail. 2025 Sep 12. doi: 10.1002/ejhf.70040. Epub ahead of print. PMID: 40938777.
Prepared by: JAJ Verdonshot and Ruth Biller