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Methods We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.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.
- genetics, medical
- neuromuscular diseases
- reproductive medicine
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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MS and BU contributed equally.
Contributors Conceptualisation: MS and MFDF; data curation: MFDF; data analysis and writing (original draft): MFDF and VL; patient recruitment and phenotypical characterisation: EG, AB, TH, MM, MJ, MI, LS, PD'O, GCCC and BU; supervision and writing (review and editing): MS and BU. MFDF and MS are also the guarantors.
Funding MS received funding from the Academy of Finland and Sydantutkimussaatio. BU received funding from the Academy of Finland and the European Joint Programme for Rare Disease.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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