Frequency of de novo variants and parental mosaicism in vascular Ehlers–Danlos syndrome

Abstract

Purpose

Vascular Ehlers–Danlos syndrome (vEDS) is a rare inherited autosomal dominant disorder caused by COL3A1 pathogenic variants. A high percentage of de novo cases has been suggested. Part of it could be due to parental mosaicism, but its frequency is unknown.

Methods

This retrospective study included a large series of COL3A1-confirmed vEDS probands with family information. The frequency of de novo cases was evaluated and the distribution of the type of variants was compared according to the mode of inheritance. The COL3A1 mosaicism was studied by deep targeted next- generation sequencing (NGS) from parental blood DNA.

Results

Out of 177 vEDS probands, 90 had a negative family history, suggesting a high rate (50.8%) of de novo pathogenic variants, enriched in the more severe COL3A1 variants (no null variant). Among those, both parental DNA were available in 36 cases and one parental DNA in 18 cases. NGS detected only one mosaicism from maternal blood DNA (allelic ratio 18%), which was confirmed in saliva (allelic ratio 22%).

Conclusion

vEDS is characterized by a high frequency of de novo pathogenic variants. Parental mosaicism is rare (2–3%), but should be systematically searched with targeted NGS, taking into account its importance in genetic counseling.

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Acknowledgements

We thank all vEDS patients and their families for their kind collaboration. We acknowledge the contribution of clinicians who assessed the patients. We thank the technicians of the genetics laboratory for their contribution to the COL3A1 genetic analysis. A.L. has obtained a 3-year PhD grant from Région Ile de France. The French Medical Reference Centre for Rare Vascular Diseases (www.maladies-vasculaires-rares.fr) is supported by the French Ministry of Health. The study was supported in part by grants from Fondation pour la Recherche Médicale (FRM), the Association Française pour les Syndromes d’Ehlers Danlos (AFSED), and the Fondation GROUPAMA. This study was also supported by Assistance Publique Hôpitaux de Paris, University Paris Descartes, and INSERM. This study included vEDS patients who are now part of a national French prospective cohort (RaDiCo SEDVasc) set up by the Rare Disease Cohorts (RaDiCo) INSERM programme funded by the plan d’Investissements d’Avenir (PIA) through the Agence Nationale pour la Recherche (ANR-IO-COHO-03-01).

Author information

Correspondence to Xavier Jeunemaitre MD, PhD.

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The authors declare no conflicts of interest.

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Cite this article

Legrand, A., Devriese, M., Dupuis-Girod, S. et al. Frequency of de novo variants and parental mosaicism in vascular Ehlers–Danlos syndrome. Genet Med 21, 1568–1575 (2019). https://doi.org/10.1038/s41436-018-0356-2

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Keywords

  • COL3A1
  • vascular Ehlers–Danlos syndrome
  • de novo variant
  • mosaicism
  • deep targeted next-generation sequencing

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