The crucial role of titin in fetal development: recurrent miscarriages and bone, heart, and muscle anomalies characterize the severe end of titinopathies spectrum

BackgroundTitin truncating variants (TTNtv) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. However, TTN is not yet included in many NGS panels for congenital musculoskeletal anomalies and dysmorphisms, and karyotype or chromosomal microarray analyses are often the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum. MethodsWe performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv. ResultsWe identified recurrent clinical features in antenatal and congenital recessive titinopathies, including fetal akinesia, arthrogryposis, facial dysmorphisms, joint, bone, and heart anomalies resembling complex, syndromic phenotypes. ConclusionWe suggest TTN to be carefully evaluated in any diagnostic process involving patients with the mentioned signs. This step will be essential to improve diagnostic performance, expand our knowledge, and optimize prenatal genetic counseling. Key messageTruncating variants in the titin gene (TTN) have been associated with a large spectrum of skeletal muscle diseases with or without cardiac involvement. The current work demonstrates that truncating biallelic variants in specific exons of TTN result in severe developmental anomalies, affecting not only the muscular systems but also bone, heart, and other organs, with a quite high rate of miscarriages and dysmorphisms. Thereby, we suggest TTN variants to be carefully evaluated in any diagnostic process involving patients with the mentioned signs.