Key result
Biallelic TTN truncating variants were associated with severe phenotypes including fetal akinesia (up to 62%), arthrogryposis (up to 85%), and facial dysmorphisms (up to 73%).
Why the study?
Prenatal cases caused by TTN defects may be missed during standard diagnostic evaluations, prompting investigation into the most severe end of the titinopathies spectrum.
Cohort (n=103)
Yes
Biallelic titin truncating variants are associated with severe syndromic phenotypes including fetal akinesia, arthrogryposis, and heart anomalies, highlighting the need for TTN evaluation in prenatal diagnostics.
Association with severe fetal phenotypes supports TTN evaluation in prenatal diagnostics; leaves open impact on outcomes.
Background Titin truncating variants (TTNtvs) 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. Often karyotype or chromosomal microarray analyses are 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 Methods We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.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 showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes. Conclusion We suggest TTN to be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling.
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Feo et al. (2023) conducted a cohort in Titinopathies (n=103). Biallelic TTN truncating variants (TTNtv) was evaluated on Recurrent clinical features including fetal akinesia, arthrogryposis, facial dysmorphisms, joint, bone and heart anomalies. Biallelic TTN truncating variants were associated with severe phenotypes including fetal akinesia (up to 62%), arthrogryposis (up to 85%), and facial dysmorphisms (up to 73%).
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