Anne Legrand1,2,3, Magali Devriese1, Sophie Dupuis-Girod4, Christophe Simian1, Annabelle Venisse1, Jean Michael Mazzella1, Karine Auribault1, Salma Adham1,2, Michael Frank1,2, Juliette Albuisson1,2,3, Xavier Jeunemaitre5,6,7. 1. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Paris, France. 2. INSERM, U970, Paris Cardiovascular Research Centre, Paris, France. 3. Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Service de Génétique, Hospices Civils de Lyon; Groupe Hospitalier Est, Bron, France. 5. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Paris, France. xavier.jeunemaitre@aphp.fr. 6. INSERM, U970, Paris Cardiovascular Research Centre, Paris, France. xavier.jeunemaitre@aphp.fr. 7. Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. xavier.jeunemaitre@aphp.fr.
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.
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.
Entities:
Keywords:
COL3A1; de novo variant; deep targeted next-generation sequencing; mosaicism; vascular Ehlers–Danlos syndrome
Authors: Justyna A Karolak; Qian Liu; Nina G Xie; Lucia R Wu; Gustavo Rocha; Susana Fernandes; Luk Ho-Ming; Ivan F Lo; David Mowat; Elizabeth K Fiorino; Morris Edelman; Joyce Fox; Denise A Hayes; David Witte; Ashley Parrott; Edwina Popek; Przemyslaw Szafranski; David Y Zhang; Pawel Stankiewicz Journal: J Mol Diagn Date: 2020-02-07 Impact factor: 5.568