Speaker: Maria Francesca Di Feo

 

Host: Prof. Heinz Jungbluth

 

Title: Decoding the impact of TTN variants: from dominant to recessive forms, from monogenic to digenic (and beyond?)

 

Abstract: Titin, the largest human protein, is a constitutive component of the sarcomere, and pathogenic TTN variants cause a remarkably broad clinical spectrum spanning skeletal and cardiac muscle disease. This seminar offers an overview on titinopathies and the impact of TTN variants, seen through the lens of a clinical geneticist.

Truncating variants are the most established cause of titinopathies, and in recent years we have learned that they must be interpreted in light of inheritance, isoform usage and exon expression, all of which shape genotype–phenotype correlation. On the other hand, pathogenicity is far harder to establish for missense variants, which frequently remain classified as variants of uncertain significance. Our recent collaborative work with colleagues at the Randall Centre has allowed us to investigate missense variants identified in patients and to show that they destabilise titin domains and trigger protein misfolding. These in-vitro analyses leave further questions open, and finer genotype–phenotype correlations remain difficult to infer. Crucially, pathogenicity can be reliably assigned only when experimental and clinical evidence are weighed together.

 

A better understanding of the mechanisms underlying individual variants is, ultimately, the prerequisite for the next chapter - including the emerging evidence of digenic and polygenic phenotypes.

 

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