Titinopathies: the comparison of clinical and genetic data help to make certain diagnosis easier

Titin is a muscle protein that gets its name from its “titanic” size. Coded by the TTN gene, it forms the essential backbone of the contractile apparatus of the muscle fiber and interacts with many other proteins in this cell compartment. It is only relatively recently that neuromuscular pathologies, in other words titinopathies, have been associated with TTN gene defects. This very large gene was in fact not very accessible for molecular diagnosis until the emergence of high throughput sequencing (NGS). Titinopathies are associated with a wide variety of clinical pictures, ranging from congenital forms to forms with later onset.

In an article published in September 2020, clinicians and geneticists from the national “Titine” consortium illustrate the difficulties in interpreting sequence variants of the TTN gene from four cases of unlabeled congenital myopathy. The absence of antibodies that can be used routinely on muscle cuts and the great variability of phenotypes are major obstacles to a definite diagnosis. This shows the importance of functional tests (such as the Western blot, reserved for the most complex cases) and of the in silico study of variants from existing databases, all associated with an in-depth analysis of the phenotype. The correlations between all these elements, associated with discussions between experts, most often make it possible to dispel doubt.

 

The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies. A Perrin, R Juntas Morales, F Rivier et al. Neuromuscul Disord. 2020 Sep 28;S0960-8966(20)30620-9. Online ahead of print.