| Title: |
The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations |
| Authors: |
Di Feo, Maria Francesca; Paramonov, Ida; Borrel, Leslie Matalonga; Töpf, Ana; Hoischen, Alexander; Beltran, Sergi; Graessner, Holm; Vissers, Lisenka; De Voer, Richarda; Van Gijn, Marielle; Balestrini, Simona; Lerche, Holger; Lesca, Gaëtan; Gayathri, Swethaa Natraj; Ellwanger, Kornelia; Cossee, Mireille; Perrin, Aurelien; Sarkozy, Anna; Bonne, Gisele; Verdonschot, Job AJ; Demidov, German; Laurie, Steven; Johari, Mridul; Solve-RD consortium; Hackman, Peter; Savarese, Marco; Udd, Bjarne |
| Source: |
Genetics in Medicine , Article 101649. (2025) (In press). |
| Publisher Information: |
Elsevier BV |
| Publication Year: |
2025 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
TTN; titinopathies; secondary findings; cardiomyopathies; neuromuscular disorders |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10217965/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10217965/1/1-s2.0-S1098360025002965-main.pdf; https://discovery.ucl.ac.uk/id/eprint/10217965/ |
| Rights: |
open |
| Accession Number: |
edsbas.9A436F2F |
| Database: |
BASE |