Di Feo, Maria Francesca;
Paramonov, Ida;
Borrel, Leslie Matalonga;
Töpf, Ana;
Hoischen, Alexander;
Beltran, Sergi;
Graessner, Holm;
... Udd, Bjarne; + view all
(2025)
The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.
Genetics in Medicine
, Article 101649. 10.1016/j.gim.2025.101649.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2025.101649 |
| Publisher version: | https://doi.org/10.1016/j.gim.2025.101649 |
| Language: | English |
| Additional information: | Under a Creative Commons license, https://creativecommons.org/licenses/by/4.0/. |
| Keywords: | TTN; titinopathies; secondary findings; cardiomyopathies; neuromuscular disorders |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217965 |
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