Key result
Biallelic truncating variants in specific exons of the TTN gene cause severe developmental anomalies affecting skeletal muscle, bone, and heart, leading to a high rate of miscarriages and dysmorphisms.
Why the study?
TTN is often omitted from NGS panels for congenital anomalies, potentially missing cases, prompting an investigation into the most severe end of the titinopathies spectrum.
Observational (n=103)
Yes
Biallelic truncating variants in the titin gene cause severe developmental anomalies affecting the muscular system, bone, and heart, highlighting the need to include TTN in prenatal genetic testing panels for these signs.
May support TTN inclusion in prenatal panels for severe fetal anomalies; leaves open validation before practice change.
Background Titin 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. Methods We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv. Results We 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. Conclusion We 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 message Truncating 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.
No takes yet. Share an insight, caveat, or question.
Feo et al. (2022) conducted an observational in Recessive titinopathies (n=103). Biallelic TTN truncating variants (TTNtv) was evaluated on Clinical features and survival rates. Biallelic truncating variants in specific exons of the TTN gene cause severe developmental anomalies affecting skeletal muscle, bone, and heart, leading to a high rate of miscarriages and dysmorphisms.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: