Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nat Med. 2023 Jun;29(6):1530-1539. doi: 10.1038/s41591-023-02364-x. Epub 2023 Jun 1.
Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies.
血管异常是血液或淋巴血管的畸形或肿瘤，可能危及生命。尽管分子靶向治疗可以挽救生命，但由于无法获得受影响的组织样本、嵌合性或测序深度不足，通常会阻碍对分子病因的识别。在 356 名血管异常患者的队列中，包括 104 名原发性复杂淋巴管异常 (pCLA) 患者，从淋巴液中分离的 CD31+细胞的 DNA 或淋巴液或血浆中的无细胞 DNA 进行了超深度测序，从而发现了致病性体细胞变异，其变异等位基因分数低至 0.15%。在 41%的 pCLA 患者和 72%的其他血管畸形患者中获得了分子诊断，包括以前未描述的遗传原因，这为 63%（43/69）的患者提供了新的治疗方法，并且在治疗的 63%（35/55）的患者中取得了改善。总的来说，这些数据支持开发基于液体活检的诊断技术，以鉴定以前未描述的基因型-表型相关性，并指导血管异常患者的医学治疗。
