Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB . Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA , which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA -derived sequences into TNXB . Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA -derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.
Competing Interests: TY, TF, YT, and TK are members of the endowed chair named “Division of Clinical Sequencing, Shinshu University School of Medicine”, which is sponsored by BML, Inc. and Life Technologies Japan Ltd., a subsidiary of Thermo Fisher Scientific Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Yamaguchi, Yamada, Nagai, Nishikubo, Koitabashi, Minami-Hori, Matsushima, Shibata, Ishiguro, Sanai, Fujikawa, Takiguchi, Matsumoto and Kosho.)