Comprehensive genetic screening for vascular Ehlers–Danlos syndrome through an amplification‐based next‐generation sequencing system

Abstract

Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification‐based next‐generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys–Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non‐Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in‐frame deletions, and one (2.9%) had a multi‐exon deletion, including two deceased patients analyzed with formalin‐fixed and paraffin‐embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Clinical features and morphology of collagen fibrils in patients with vascular Ehlers–Danlos based on electron microscopy

“…Based on the relevant literature, the pathophysiology of vEDS remains unclear. In our previous study, we found no correlation between decreased levels of collagen III produced from cultured fibroblasts, gene mutations, and clinical symptoms among Japanese patients with vEDS (Shimaoka et al, 2010;Yamaguchi et al, 2023). Notably, only nonsense mutations are known to be of mild type and are associated with a high survival rate; however, these mutations are noted in only a few cases of vEDS (Byers et al, 2017).…”

“…The exclusion criteria were as follows: patients who did not undergo genetic analysis for COL3A1; those aged <17 years (excluding those with asymptomatic diagnoses based on the Frontiers in Genetics frontiersin.org information of their relatives); those who did not undergo skin biopsy for sample collection from unexposed upper arms; those who did not undergo analysis for the expression level of procollagen III in cultured fibroblasts; those without full information of clinical symptoms in the medical record; and those who had reduced procollagen III levels but no COL3A1 mutations (Supplementary Figure S1). Notably, data regarding some cases of vEDS were obtained from our previous reports (Hayashi et al, 2020;Kida et al, 2022;Yamaguchi et al, 2023). Two or more dermatologists and one geneticist with >15 years of experience recorded the presence of clinical symptoms during diagnosis based on the clinical diagnostic criteria reported in a previous study (Beighton et al, 1998;Malfait et al, 2017).…”

Structural genomic variants in thoracic aortic disease

“…FBN1 encodes fibrillin-1 that functions as a structural component in the extracellular matrix and regulates growth factor signalling pathways [ 20 ]. A study by Yamaguchi et al [ 21 ] identified one multiexon deletion of COL3A1 (alpha 1 chain of type III collagen) in a patient with vascular Ehlers-Danlos syndrome (vEDS; MIM #130050). Although this specific patient did not present with aortic or arterial diseases (yet), these features are often present in vEDS [ 21 ].…”

“…A study by Yamaguchi et al [ 21 ] identified one multiexon deletion of COL3A1 (alpha 1 chain of type III collagen) in a patient with vascular Ehlers-Danlos syndrome (vEDS; MIM #130050). Although this specific patient did not present with aortic or arterial diseases (yet), these features are often present in vEDS [ 21 ]. Kempers et al [ 22 ] described three patients with a deletion of varying size including both COL3A1 and COL5A2 (alpha 2 chain of type V collagen).…”

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

“…Next-generation sequencing (NGS) panel-based genetic screening is a useful approach for differentiating multiple subtypes of EDS and other HCTDs with overlapping clinical manifestations ( Yamaguchi et al, 2023 ). However, the presence of the pseudogene TNXA , which is >97% identical to the 3′end of TNXB (exons 32–44), makes it challenging to detect TNXB variants by conventional NGS analysis ( Demirdas et al, 2017 ).…”