At the Scientific Retreat MAGI in Precision Medicine and Omics Sciences held at Villa Hoffmann in Merano (17–21 November 2025), cardiovascular medicine was one of the central themes of discussion. Particular attention was given to rare congenital conditions, including structural heart defects, inherited cardiomyopathies, aneurysms of the great vessels and complex vascular malformations. These disorders are increasingly viewed as the result of an interplay between Mendelian variants and more complex genetic and environmental influences. Within this framework, researchers and clinicians from MAGI and the Cardiology Unit of the University of Brescia, directed by Prof. Savina Nodari (who was not personally present but represented by members of her research group), considered how multi-omics tools, artificial intelligence and clinical expertise might gradually be combined in a more structured and informative way.
The collaboration with the University of Brescia is centred on congenital heart defects and cardiomyopathies in children and young adults, as well as on selected vascular disorders that may coexist with, or mimic, primary cardiac disease. Experience with next-generation sequencing panels and, in selected cases, exome or genome analysis was presented as a basis on which to develop more refined diagnostic strategies for Mendelian cardiac and vascular diseases, including hypertrophic, dilated and arrhythmogenic cardiomyopathies, inherited channelopathies and familial forms of aortic aneurysm. MAGI’s bioinformatics teams illustrated variant interpretation pipelines designed to detect single-nucleotide variants and copy-number changes across broad panels of cardiac and vascular genes and to classify them according to current international criteria. Clinicians from Prof. Nodari’s group contributed case-based observations on situations in which molecular reports leave important questions open, for example when variants of uncertain significance are identified or when genetic findings do not fully account for the clinical and imaging picture. Rather than proposing definitive solutions, the discussion emphasised the importance of joint re-evaluation of challenging cases, iterative feedback between laboratory and clinic, and documentation practices that facilitate revision of classifications as new data become available.
A specific point of interest was how multi-omics data might, in the future, help to refine the interpretation of Mendelian variants in both cardiac and vascular phenotypes. MAGI researchers described exploratory work in which genomic findings are being considered together with metabolomic and, where available, proteomic and transcriptomic readouts. For cardiomyopathies, targeted metabolomic profiles related to energy production, lipid handling and redox balance are being studied as possible correlates of variants in sarcomeric, ion-channel or desmosomal genes. For congenital aneurysms and vascular malformations, attention is beginning to focus on pathways involved in extracellular-matrix remodelling, endothelial signalling and smooth-muscle function. These projects are still at an early stage and are intended primarily to generate hypotheses on how systemic molecular perturbations observed in blood or tissue samples might relate to specific genetic defects and to differences in disease severity or progression.
In parallel, the retreat provided an opportunity to discuss the potential role of artificial intelligence in cardiogenetics and vasculogenetics. MAGI’s data-science group presented preliminary work on machine-learning tools designed to support, rather than replace, expert assessment. These systems are being tested to prioritise variants by integrating classical annotations (conservation indices, in silico predictions, population frequencies) with structured phenotypic descriptors, electrocardiographic measures, echocardiographic parameters and, where relevant, imaging data from CT or MRI of the great vessels. Clustering and pattern-recognition methods are also being explored to group patients with similar geno-phenotypic profiles, potentially highlighting subgroups that might warrant closer clinical observation or more intensive follow-up. Participants agreed that such tools should be considered decision-support instruments whose performance, transparency and potential biases will require careful evaluation before they can be incorporated into routine cardiogenetic or vascular practice.
The discussions on vascular disease drew on the broader experience of specialists in vascular surgery and angiology, in particular the work of Prof. Raul Mattassi and Dr Cavalca, whose group was not present in Merano but whose clinical and scientific activity was extensively reviewed. Their work on complex vascular malformations and aneurysms of the large vessels – including combined arterial–venous malformations and syndromic forms – was taken as an example of how detailed imaging, careful clinical classification and molecular analysis might, in the future, be brought together in a more integrated fashion. In this context, participants considered how methodological approaches being developed for congenital heart disease could be adapted to vascular anomalies, and how shared registries and common data standards might facilitate collaboration between cardiologists, vascular surgeons, angiologists and geneticists.
Across all these topics, deep phenotyping emerged as an essential complement to genetics and other omics layers. Echocardiography, cardiac MRI, electrocardiography, vascular imaging and standard clinical parameters were seen as crucial for anchoring molecular hypotheses in observable patient trajectories. MAGI researchers outlined work in progress aimed at linking these clinical descriptors with genomic and metabolomic data, with the hypothesis that specific combinations of features might, in time, help to distinguish subgroups of congenital heart disease or vascular malformation with different prognoses. The potential use of polygenic risk scores in borderline or unexplained paediatric cases was mentioned as another line of investigation, to be approached cautiously and with particular attention to validation and communication to families.
Overall, the cardiovascular discussions in Merano portrayed a field in which multi-omics and computational approaches are beginning to be tested as possible complements to conventional clinical reasoning, rather than as substitutes for it. The exchanges between MAGI, the team from the University of Brescia led by Prof. Savina Nodari, and the wider vascular community represented by the work of Prof. Raul Mattassi and Dr Cavalca were not intended to introduce new diagnostic algorithms or therapeutic protocols. Instead, they helped to clarify shared questions, compare preliminary experiences and identify realistic avenues for collaborative studies. In this sense, the retreat contributed to outlining a cautious yet forward-looking roadmap for integrating genomics, multi-omics and artificial-intelligence tools into the study of congenital cardiovascular and vascular disorders, with the longer-term aim of improving understanding of these complex conditions and, over time, supporting more informed care for the patients and families involved.