Splicing Alterations Associated with Multiple Homozygous TNXB Variants in a Patient with Suspected Classical-Like Ehlers–Danlos Syndrome
4 affiliations
- 1Graduate School of Science and Engineering, Kindai University, Higashi-Osaka, Japan
- 2Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan
- 3Department of Clinical Genetics, Kindai University Hospital, Sakai, Japan
- 4Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502 Japan
Abstract
Ehlers–Danlos syndrome (EDS) comprises a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Classical-like EDS (clEDS) is typically associated with pathogenic biallelic variants in TNXB. The patient showed generalized joint hypermobility involving the knees, fingers, elbows, and feet, along with soft, pliable skin. She had a history of three dislocations of the right elbow and one dislocation of the left elbow. She also reported orthostatic dizziness and chronic constipation, suggesting possible autonomic nervous system involvement. Cardiovascular assessment detected mild mitral valve regurgitation. Based on these findings, hypermobility syndrome or EDS was suspected, and gene panel testing was conducted for classical and pseudo-classical EDS. The patient was found to be homozygous for multiple TNXB (NM_001365276.2) variants, including c.11,925 + 6 C > G, c.12,156 C > G (p. Arg4052=), c.12,210 + 5G > A, c.12,210 + 39dup, and c.12,210 + 43T > G, and also carried a mosaic variant c.8012 C > T (p. Ala2671Val). To investigate the potential effects of these variants on splicing, RT-PCR using peripheral blood RNA and in vitro minigene splicing assays were performed. Analysis of the patient-derived cDNA and cDNA derived from mutant minigenes revealed alternative splicing leading to intron 40 retention alongside the normal transcript. Intron 40 retention was more pronounced with multiple variants and was most prominently associated with c.12,210 + 5G > A in the minigene assays. These results suggest that c.12,210 + 5G > A can influence TNXB splicing, generating in-frame transcripts. The aberrant transcripts are predicted to affect the fibrinogen C-terminal domain. Although the clinical significance of these variants remains uncertain, these findings highlight the importance of integrating population frequency data, clinical assessment, and functional analyses when interpreting uncertain TNXB variants in patients with suspected clEDS.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10528-026-11416-z.
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BibTeX
@article{imanaka2026splicing,
title = {{Splicing Alterations Associated with Multiple Homozygous TNXB Variants in a Patient with Suspected Classical-Like Ehlers–Danlos Syndrome}},
author = {Bunta Imanaka and Yuiko Hasegawa and Kazumi Kawato and Yuma Kimoto and Itsuki Oda and Nobuhiko Okamoto and Kazumasa Saigoh and Mina Nakama},
journal = {Biochemical Genetics},
year = {2026},
month = jun,
doi = {10.1007/s10528-026-11416-z},
url = {https://doi.org/10.1007/s10528-026-11416-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Splicing Alterations Associated with Multiple Homozygous TNXB Variants in a Patient with Suspected Classical-Like Ehlers–Danlos Syndrome
AU - Bunta Imanaka
AU - Yuiko Hasegawa
AU - Kazumi Kawato
AU - Yuma Kimoto
AU - Itsuki Oda
AU - Nobuhiko Okamoto
AU - Kazumasa Saigoh
AU - Mina Nakama
PY - 2026
DA - 2026/06/15
JO - Biochemical Genetics
DO - 10.1007/s10528-026-11416-z
UR - https://doi.org/10.1007/s10528-026-11416-z
AB - Ehlers–Danlos syndrome (EDS) comprises a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Classical-like EDS (clEDS) is typically associated with pathogenic biallelic variants in TNXB. The patient showed generalized joint hypermobility involving the knees, fingers, elbows, and feet, along with soft, pliable skin. She had a history of three dislocations of the right elbow and one dislocation of the left elbow. She also reported orthostatic dizziness and chronic constipation, suggesting possible autonomic nervous system involvement. Cardiovascular assessment detected mild mitral valve regurgitation. Based on these findings, hypermobility syndrome or EDS was suspected, and gene panel testing was conducted for classical and pseudo-classical EDS. The patient was found to be homozygous for multiple TNXB (NM_001365276.2) variants, including c.11,925 + 6 C > G, c.12,156 C > G (p. Arg4052=), c.12,210 + 5G > A, c.12,210 + 39dup, and c.12,210 + 43T > G, and also carried a mosaic variant c.8012 C > T (p. Ala2671Val). To investigate the potential effects of these variants on splicing, RT-PCR using peripheral blood RNA and in vitro minigene splicing assays were performed. Analysis of the patient-derived cDNA and cDNA derived from mutant minigenes revealed alternative splicing leading to intron 40 retention alongside the normal transcript. Intron 40 retention was more pronounced with multiple variants and was most prominently associated with c.12,210 + 5G > A in the minigene assays. These results suggest that c.12,210 + 5G > A can influence TNXB splicing, generating in-frame transcripts. The aberrant transcripts are predicted to affect the fibrinogen C-terminal domain. Although the clinical significance of these variants remains uncertain, these findings highlight the importance of integrating population frequency data, clinical assessment, and functional analyses when interpreting uncertain TNXB variants in patients with suspected clEDS. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10528-026-11416-z.
SN - 0006-2928
SN - 1573-4927
ER -