Abstract：
BACKGROUND: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B.
OBJECTIVE: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers.
METHODS: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique.
RESULTS: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather.
CONCLUSIONS: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.
OBJECTIVE: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers.
METHODS: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique.
RESULTS: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather.
CONCLUSIONS: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.
摘要：
背景：在新诊断的B型血友病病例中，散发性病例的比例通常为重症病例的50％和中度/轻度病例的25％。然而,由于家族史而推测为零星的病例可能并不总是零星的。关于血友病B的镶嵌性的病例报道很少。
目的：本研究旨在通过单倍型标记在明确的散发性血友病B病例队列中追踪致病变异的起源。它还旨在确定假定的非携带者母亲的镶嵌频率。
方法：研究组为40个家庭，每个人都有一个散发性的B型血友病病例，通过Sanger测序分析了两到三代，单体分型和使用敏感的液滴数字聚合酶链反应(ddPCR)技术。
结果：在31/40（78％）的家庭中，这位母亲携带着和她儿子相同的致病变种,而Sanger测序显示，9/40（22％）的母亲没有携带这种变异。在这些变体中，使用ddPCR技术显示2/9（22％）是马赛克。16/21携带者母亲，有三代的样本，有一个从头致病变异，其中14个来自健康的外祖父。
结论：散发性乙型血友病病例中致病变异的起源最常见于X染色体上，很少，来自外婆。似乎发现花叶病雌性的频率与A型血友病相同，但致病变异的百分比较低。
目的：本研究旨在通过单倍型标记在明确的散发性血友病B病例队列中追踪致病变异的起源。它还旨在确定假定的非携带者母亲的镶嵌频率。
方法：研究组为40个家庭，每个人都有一个散发性的B型血友病病例，通过Sanger测序分析了两到三代，单体分型和使用敏感的液滴数字聚合酶链反应(ddPCR)技术。
结果：在31/40（78％）的家庭中，这位母亲携带着和她儿子相同的致病变种,而Sanger测序显示，9/40（22％）的母亲没有携带这种变异。在这些变体中，使用ddPCR技术显示2/9（22％）是马赛克。16/21携带者母亲，有三代的样本，有一个从头致病变异，其中14个来自健康的外祖父。
结论：散发性乙型血友病病例中致病变异的起源最常见于X染色体上，很少，来自外婆。似乎发现花叶病雌性的频率与A型血友病相同，但致病变异的百分比较低。
