Comprehensive genetic screening for vascular Ehlers-Danlos syndrome through an amplification-based next-generation
Tomomi Yamaguchi1,2,3, Shujiro Hayashi4, Daisuke Hayashi5
1Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
Insights
Vascular Ehlers-Danlos syndrome (vEDS) is diagnosed by finding COL3A1 gene variants. This study identified COL3A1 variants in 32.4% of Asian patients suspected of vEDS, using advanced sequencing methods.
Area of Science:
- Genetics
- Vascular Biology
- Connective Tissue Disorders
Background:
- Vascular Ehlers-Danlos syndrome (vEDS) is a life-threatening hereditary connective tissue disorder.
- Diagnosis relies on identifying heterozygous variants in the COL3A1 gene.
- Limited data exists on vEDS in Asian populations.
Purpose of the Study:
- To investigate the genetic basis of vEDS in an Asian cohort.
- To evaluate the efficacy of amplification-based next-generation sequencing for detecting COL3A1 variants and copy number variations.
Main Methods:
- Analysis of 429 patients with suspected hereditary connective tissue disorders (HCTDs) using custom gene panels.
- Next-generation sequencing (NGS) with amplification-based methods.
- Specific evaluation of copy number variations (CNVs).
Main Results:
- 101 patients were suspected of vEDS; 33 (32.4%) had confirmed COL3A1 variants.
- COL3A1 variants were also found in two patients with Loeys-Dietz syndrome/familial thoracic aortic aneurysm and dissection.
- The majority of variants were missense substitutions (Glycine or non-Glycine), splice site alterations, nonsense variants, or deletions.
Conclusions:
- NGS with custom panels is effective for diagnosing vEDS and detecting diverse COL3A1 variants, including CNVs, in various sample types.
- This study represents the largest Asian case series for vEDS and provides valuable genetic insights into the condition within this population.
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.
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