Department of Clinical Sciences Lund - Paediatrics, Lund University, Lund, Sweden.
Department of Paediatrics, Skåne University Hospital, Lund, Sweden.
Haemophilia. 2024 May;30(3):774-779. doi: 10.1111/hae.15019. Epub 2024 Apr 17.
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.
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.
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.
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.
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.
新诊断的乙型血友病患者中，散发病例的比例通常为重型病例的 50%和中/轻型病例的 25%。然而，由于家族史而被认为是散发病例的情况并不总是如此。关于乙型血友病镶嵌现象的病例报告很少。
本研究旨在通过单体型分析标记物追踪明确界定的乙型血友病散发病例队列中致病变异的来源，并确定假定非携带者母亲中镶嵌现象的频率。
研究组为 40 个家系，每个家系均对 2-3 代的乙型血友病散发病例进行 Sanger 测序、单体型分析和使用敏感的数字 PCR（ddPCR）技术。
在 31/40（78%）的家系中，母亲携带与其儿子相同的致病变异，而 Sanger 测序显示 9/40（22%）的母亲未携带该变异。在这些变异中，9/40（22%）的母亲通过 ddPCR 技术显示为镶嵌现象。16/21 位携带母亲的样本来自三代人，其中 14 个有新的致病性变异，其中 14 个源自健康的外祖父。
乙型血友病散发病例中致病变异的来源通常来自于母亲的外祖父的 X 染色体，或者较少情况下来自于母亲的外祖母。镶嵌女性似乎与甲型血友病的频率相同，但致病性变异的比例较低。
