Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome
Abstract Background Vascular Ehlers‐Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
|
| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2240 |
| _version_ | 1827820502023929856 |
|---|---|
| author | Won Young Heo Shin Yi Jang Taek Kyu Park Chang‐Seok Ki Jong‐Won Kim Duk‐Kyung Kim Ja‐Hyun Jang |
| author_facet | Won Young Heo Shin Yi Jang Taek Kyu Park Chang‐Seok Ki Jong‐Won Kim Duk‐Kyung Kim Ja‐Hyun Jang |
| author_sort | Won Young Heo |
| collection | DOAJ |
| description | Abstract Background Vascular Ehlers‐Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report 2 patients with vEDS who were not diagnosed by conventional Sanger sequencing. Methods We performed either targeted panel or whole‐genome sequencing. Complementary DNA (cDNA) sequencing was performed using cultured skin fibroblasts. Sanger sequencing of DNA was performed for the confirmation of breakpoints in the case of exon deletion. We also evaluated the sensitivity of the splicing prediction tool, SpliceAI. Results An exon 27 deletion was suspected on targeted panel sequencing of 1 patient. The deletion was confirmed using cDNA sequencing (r.1870_1923del) and breakpoints were confirmed (c.1870‐109_1923+10del). On targeted panel sequencing in the other patient, we found a novel intronic variant of c.1149+6T>C that leads to skipping of exon 16 (r.1051_1149del) by cDNA sequencing. SpliceAI showed 98.8% sensitivity for known splicing variants in COL3A1. Conclusion Our study highlights the necessity of a comprehensive approach to the genetic diagnosis of vEDS. In addition, cDNA sequencing was useful as an auxiliary method, especially considering the limited sensitivity of the splicing prediction tool. |
| first_indexed | 2024-03-12T01:28:46Z |
| format | Article |
| id | doaj.art-df00328144864b81b29d23934d4cc772 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-12T01:28:46Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-df00328144864b81b29d23934d4cc7722023-09-12T09:57:08ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-09-01119n/an/a10.1002/mgg3.2240Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndromeWon Young Heo0Shin Yi Jang1Taek Kyu Park2Chang‐Seok Ki3Jong‐Won Kim4Duk‐Kyung Kim5Ja‐Hyun Jang6Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South KoreaDivision of Cardiology, Department of Medicine, Samsung Medical Center Heart Vascular Stroke Institute, Sungkyunkwan University School of Medicine Seoul South KoreaDivision of Cardiology, Department of Medicine, Samsung Medical Center Heart Vascular Stroke Institute, Sungkyunkwan University School of Medicine Seoul South KoreaGC Genome Yongin South KoreaDepartment of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South KoreaDivision of Cardiology, Department of Medicine, Samsung Medical Center Heart Vascular Stroke Institute, Sungkyunkwan University School of Medicine Seoul South KoreaDepartment of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South KoreaAbstract Background Vascular Ehlers‐Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report 2 patients with vEDS who were not diagnosed by conventional Sanger sequencing. Methods We performed either targeted panel or whole‐genome sequencing. Complementary DNA (cDNA) sequencing was performed using cultured skin fibroblasts. Sanger sequencing of DNA was performed for the confirmation of breakpoints in the case of exon deletion. We also evaluated the sensitivity of the splicing prediction tool, SpliceAI. Results An exon 27 deletion was suspected on targeted panel sequencing of 1 patient. The deletion was confirmed using cDNA sequencing (r.1870_1923del) and breakpoints were confirmed (c.1870‐109_1923+10del). On targeted panel sequencing in the other patient, we found a novel intronic variant of c.1149+6T>C that leads to skipping of exon 16 (r.1051_1149del) by cDNA sequencing. SpliceAI showed 98.8% sensitivity for known splicing variants in COL3A1. Conclusion Our study highlights the necessity of a comprehensive approach to the genetic diagnosis of vEDS. In addition, cDNA sequencing was useful as an auxiliary method, especially considering the limited sensitivity of the splicing prediction tool.https://doi.org/10.1002/mgg3.2240COL3A1mRNA sequencingSpliceAIvascular Ehlers‐Danlos syndromewhole‐genome sequencing |
| spellingShingle | Won Young Heo Shin Yi Jang Taek Kyu Park Chang‐Seok Ki Jong‐Won Kim Duk‐Kyung Kim Ja‐Hyun Jang Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome Molecular Genetics & Genomic Medicine COL3A1 mRNA sequencing SpliceAI vascular Ehlers‐Danlos syndrome whole‐genome sequencing |
| title | Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome |
| title_full | Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome |
| title_fullStr | Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome |
| title_full_unstemmed | Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome |
| title_short | Identification of two novel COL3A1 variants in patients with vascular Ehlers‐Danlos syndrome |
| title_sort | identification of two novel col3a1 variants in patients with vascular ehlers danlos syndrome |
| topic | COL3A1 mRNA sequencing SpliceAI vascular Ehlers‐Danlos syndrome whole‐genome sequencing |
| url | https://doi.org/10.1002/mgg3.2240 |
| work_keys_str_mv | AT wonyoungheo identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT shinyijang identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT taekkyupark identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT changseokki identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT jongwonkim identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT dukkyungkim identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome AT jahyunjang identificationoftwonovelcol3a1variantsinpatientswithvascularehlersdanlossyndrome |