Identification of two novel COL3A1 variants in patients with vascular Ehlers-Danlos syndrome
© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Molecular genetics & genomic medicine - 11(2023), 9 vom: 17. Sept., Seite e2240 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Heo, Won Young [VerfasserIn] |
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| Links: |
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| Themen: |
COL3A1 |
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| Anmerkungen: |
Date Completed 13.09.2023 Date Revised 18.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/mgg3.2240 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM359617506 |
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| 500 | |a Date Revised 18.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
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| 520 | |a © 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a COL3A1 | |
| 650 | 4 | |a SpliceAI | |
| 650 | 4 | |a mRNA sequencing | |
| 650 | 4 | |a vascular Ehlers-Danlos syndrome | |
| 650 | 4 | |a whole-genome sequencing | |
| 650 | 7 | |a DNA, Complementary |2 NLM | |
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| 700 | 1 | |a Kim, Jong-Won |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Duk-Kyung |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Ja-Hyun |e verfasserin |4 aut | |
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