Purpose: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. Methods: We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. Results: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy. Conclusion: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.
The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations / Di Feo, M.F., Paramonov, I., Borrel, L.M., Töpf, A., Hoischen, A., Beltran, S., Graessner, H., Vissers, L., de Voer, R., van Gijn, M., Balestrini, S., Lerche, H., Lesca, G., Gayathri, S.N., Ellwanger, K., Cossee, M., Perrin, A., Sarkozy, A., Bonne, G., Verdonschot, J.A.J., et al.. - In: GENETICS IN MEDICINE. - ISSN 1098-3600. - ELETTRONICO. - (2025), pp. 0-0. [10.1016/j.gim.2025.101649]
The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations
Balestrini, Simona;
2025
Abstract
Purpose: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. Methods: We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. Results: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy. Conclusion: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.
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