We are pleased to highlight a new study published in Genetics in Medicine by Maria Francesca Di Feo, Marco Savarese, Bjarne Udd, and colleagues from the Solve-RD consortium, supported in part by CoMPaSS-NMD.

As next-generation sequencing becomes more common, interpreting rare variants in TTN—the largest gene in the human body—poses a significant clinical challenge. This study analyzed genomic data from 18,462 individuals within the European Solve-RD rare disease network. Key findings include:

• Skeletal Myopathy Enrichment: A significant 3.8% prevalence of TTN truncating variants (TTNtv) was found in the neuromuscular disease cohort, primarily consisting of unsolved cases, signaling that many titinopathies remain underdiagnosed.

• Cardiac Penetrance Evaluation: Around 0.5% of the entire cohort carried a TTNtv in highly expressed cardiac exons, with an estimated adult disease penetrance of roughly 10.4%.

• Clinical Frameworks: The authors provide updated workflows and actionable recommendations to guide clinicians through genetic counseling, risk management, and reproductive planning for both primary and secondary TTN findings.

This collaborative work underscores the vital need for standardized screening and international cooperation to solve missing heritability in muscle and heart disorders.