Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Paris, France.
INSERM, U970, Paris Cardiovascular Research Centre, Paris, France.
Genet Med. 2019 Jul;21(7):1568-1575. doi: 10.1038/s41436-018-0356-2. Epub 2018 Nov 26.
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.
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.
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%).
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.
血管型埃勒斯-当洛斯综合征（vEDS）是一种罕见的常染色体显性遗传性疾病，由 COL3A1 致病性变异引起。已提出很高比例的新生病例可能是由于父母镶嵌现象，但其频率尚不清楚。
本回顾性研究纳入了一系列 COL3A1 确诊的有家族史的 vEDS 先证者。评估了新生病例的频率，并根据遗传方式比较了变异类型的分布。通过对父母血液 DNA 进行深度靶向下一代测序（NGS）来研究 COL3A1 镶嵌现象。
在 177 名 vEDS 先证者中，90 名有阴性家族史，提示新生致病性变异的发生率较高（50.8%），且在更严重的 COL3A1 变异中更为丰富（无缺失变异）。其中，36 例可获得双亲的 DNA，18 例可获得单亲的 DNA。NGS 仅从母亲血液 DNA 中检测到 1 例镶嵌现象（等位基因比例为 18%），在唾液中得到了证实（等位基因比例为 22%）。
vEDS 的特点是新生致病性变异的频率较高。父母镶嵌现象罕见（2-3%），但应系统地通过靶向 NGS 进行搜索，并考虑其在遗传咨询中的重要性。
