Molecular autopsies are transforming the way we understand sudden cardiac death (SCD), especially in young individuals where conventional pathology often leaves questions unanswered. With the continuous refinement of sequencing technologies, genetic variants that were once invisible or dismissed as inconsequential are now entering the spotlight.

In a recent case, our team identified a rare variant that, just a few years ago, would likely have remained undetected or overlooked. What made the difference was not only the sequencing depth, but also the availability of functional tools to evaluate the variant’s effect. Through carefully designed follow-up studies, we collected evidence pointing toward a possible mechanistic role in arrhythmogenesis.

This shift resonates with the goals of our NextGen consortium, which builds AI-based frameworks to integrate genomic data with clinical and phenotypic information. By connecting sequencing results to multimodal datasets, NextGen aims to refine variant interpretation, improve individualized risk stratification, and provide decision support for patients and families affected by SCD.

This experience shifted the conversation within our multidisciplinary team. Instead of asking whether the variant is clinically relevant, the discussion evolved toward how it could contribute to the observed phenotype. This subtle but important transition illustrates a broader movement in cardiovascular genetics: away from a binary classification of variants toward a more nuanced, mechanistic understanding.

The challenge now lies in keeping our interpretative frameworks aligned with technological progress. As sequencing platforms advance, the sheer volume and complexity of data demand updated models for classification, validation, and integration into clinical decision-making.

Ultimately, each case underscores the same lesson: sequencing does not just add data, it deepens the story. To fully realize its potential, we must adapt our tools, collaborations, and mindsets, ensuring that discoveries at the molecular level translate into meaningful insights for patients and families affected by SCD.

Prof. Silke Kauferstein

Universitätsklinikum Frankfurt

Institut für Rechtsmedizin

Leitung Zentrum für plötzlichen Herztod und Kardiogenetik