A comprehensive framework for the interpretation of TTN missense variants - PubMed
3 hours ago
- #Genetic diagnostics
- #TTN missense variants
- #Titinopathies
- Missense variants in TTN present challenges in genetic diagnostics due to their high frequency and the gene's complexity.
- The study focuses on rare TTN missense variants in trans with truncating variants (TTNtv) in myopathy cases.
- Clinical data were collected globally, and in silico predictions used AlphaMissense with MAF < 0.010 and score ≥ 0.792.
- Functional assays showed proline mutations in Ig domains caused impaired folding and aggregation.
- The variant p.(Gln7023Pro) was found in 5 families, indicating a common ancestor, and classified as likely pathogenic.
- The study proposes a framework integrating clinical, computational, and functional evidence for TTN missense variant interpretation.
- Tailored guidelines and global data sharing are needed for improved diagnostic accuracy.