https://scholars.lib.ntu.edu.tw/handle/123456789/623937
標題: | Origin and timing of de novo variants implicated in type 2 von Willebrand disease | 作者: | MING CHEN MING-CHING SHEN Chang, Shun-Ping Ma, Gwo-Chin Huang, Ying-Chih Lin, Ching-Yeh |
關鍵字: | de novo variant; type 2 von Willebrand disease; von Willebrand disease | 公開日期: | 13-十月-2022 | 出版社: | WILEY | 來源出版物: | Journal of cellular and molecular medicine | 摘要: | Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/623937 | ISSN: | 1582-1838 | DOI: | 10.1111/jcmm.17563 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。