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Truncating variants in the penultimate exon of TGFBR1 escaping nonsense-mediated mRNA decay cause Loeys-Dietz syndrome


Pathogenic variants in TGFBR1 are a common cause of Loeys-Dietz syndrome (LDS) characterized by life-threatening aortic and arterial disease. Generally, these are missense changes in highly conserved amino acids in the serine–threonine kinase domain. Conversely, nonsense, frameshift, or specific missense changes in the ligand-binding extracellular domain cause multiple self-healing squamous epithelioma (MSSE) lacking the cardiovascular phenotype. Here, we report on two novel variants in the penultimate exon 8 of TGFBR1 were identified in 3 patients from two unrelated LDS families: both were predicted to cause frameshift and premature stop codons (Gln448Profs*15 and Cys446Asnfs*4) resulting in truncated TGFBR1 proteins lacking the last 43 and 56 amino acid residues, respectively. These were classified as variants of uncertain significance based on current criteria. Transcript expression analyses revealed both mutant alleles escaped nonsense-mediated mRNA decay. Functional characterization in patient’s dermal fibroblasts showed paradoxically enhanced TGFβ signaling, as observed for pathogenic missense TGFBR1 changes causative of LDS. In summary, we expanded the allelic repertoire of LDS-associated TGFBR1 variants to include truncating variants escaping nonsense-mediated mRNA decay. Our data highlight the importance of functional studies in variants interpretation for correct clinical diagnosis.

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Fig. 1: Clinical, molecular and protein modeling data of the herein reported families harboring two distinct truncating variants in the TGFBR1 gene.
Fig. 2: Molecular and cellular studies.

Data availability

The novel TGFBR1 variants identified in this study were submitted to the Leiden Open Variation Database (LOVD;, with IDs: #0000785357 and #0000785358. Additional data and materials are available from the corresponding author on reasonable request, subject to compliance with our obligations under human research ethics.


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We wish to thank the families for kind availability to participate to this study and for allowing us to share these findings within the scientific community. This work is dedicated to the memory of Letizia Camerota, brilliant and devoted medical geneticist of L’Aquila University, Italy.


VC, NZ, MC, and MR, also thank the Fazzo Cusan family for its generous support. LS is supported by a grant from Fondazione IRP Città della Speranza, Padova. FBr and FA are funded by intramural Grant of the University of L’Aquila (FFO2020). FBr and PF were supported by funding of the Italian Ministry of Health [ricerca corrente].

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Authors and Affiliations



PF, RM, VC, NZ, LDL, EDD and RI performed mRNA expression analyses, functional studies, immunofluorescence microscopy and western blotting; VC, CR, FBo, ADD, LS and MR performed the molecular genetic investigations; CR, FBo and CDL performed the bioinformatic analysis of the data and revised the literature; CDL, RDP, LS and FBr, performed the clinical assessment; FA performed protein modeling studies; EDC performed the imaging assessment; MC, FBr and MR had a major role in acquiring and processing clinical and molecular data, in the study concept and in the revision and finalization of the manuscript with all the authors’ input. All authors read and approved the final manuscript.

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Correspondence to Francesco Brancati.

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The authors declare no competing interests.

Ethics statement

The Internal Review Board of the University of L’Aquila approved this study (Project code PGR00919). Written informed consent for genetic testing and use of peripheral blood, skin biopsy, and clinical data for research and publication purposes were obtained from all the patients or their legal guardians.

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Fortugno, P., Monetta, R., Cinquina, V. et al. Truncating variants in the penultimate exon of TGFBR1 escaping nonsense-mediated mRNA decay cause Loeys-Dietz syndrome. Eur J Hum Genet (2023).

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