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

Tomomi Yamaguchi; Kazuo Yamada; So Nagai; Toshiya Nishikubo; Norimichi Koitabashi; Masako Minami-Hori; Masaaki Matsushima; Yuka Shibata; Hiroki Ishiguro; Hiromi Sanai; Tomomi Fujikawa; Yuri Takiguchi; Ken-Ichi Matsumoto; Tomoki Kosho

doi:10.3389/fgene.2023.1234804

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

Front Genet. 2023 Aug 30:14:1234804. doi: 10.3389/fgene.2023.1234804. eCollection 2023.

Authors

Tomomi Yamaguchi^{1

2

3}, Kazuo Yamada^{4

5}, So Nagai^{1

3

6}, Toshiya Nishikubo⁷, Norimichi Koitabashi⁸, Masako Minami-Hori⁹, Masaaki Matsushima^{10

11}, Yuka Shibata¹¹, Hiroki Ishiguro¹², Hiromi Sanai^{13

14}, Tomomi Fujikawa³, Yuri Takiguchi³, Ken-Ichi Matsumoto⁴, Tomoki Kosho^{1

2

3

15}

Affiliations

¹ Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan.
² Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
³ Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan.
⁴ Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, Japan.
⁵ Department of Legal Medicine, Faculty of Medicine, Shimane University, Izumo, Japan.
⁶ Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD (Next-Generation Super Doctor) Project, Matsumoto, Japan.
⁷ Division of Neonatal Intensive Care, Nara Medical University, Nara, Japan.
⁸ Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
⁹ Division of Dermatology, Asahikawa City Hospital, Asahikawa, Japan.
¹⁰ Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹¹ Division of Clinical Genetics, Hokkaido University Hospital, Sapporo, Japan.
¹² Department of Clinical Genetics, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.
¹³ Department of Obstetrics and Gynecology, Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan.
¹⁴ Department of Medical Genetics, Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan.
¹⁵ Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan.

Abstract

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.

Keywords: Ehlers-Danlos syndrome; TNXB; classical-like; connective tissue disorder; tenascin-X.

Grants and funding

This study was supported by the Grant-in-Aid for Young Scientists from The Japan Society for the Promotion of Science, Japan (19K17795; 2019–2023 to TY); Research on Intractable Diseases (09835303, 10801776, 11948954; 2009–2011 to TK); the Research Program on Policy of Measures for Intractable/Rare Diseases, Ministry of Health, Labour and Welfare, Japan (20316866; 2020–2022 to TK); the Program for an Integrated Database of Clinical and Genomic Information (16818213; 2016–2020 to TK); and the Initiative on Rare and Undiagnosed Diseases, Japan Agency for Medical Research and Development (21445007; 2018–2020 to TK).