Somatic mosaicism in hemophilia A: A fairly common event
Somatic mosaicism in hemophilia A: A fairly common event
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DOI：
10.1086/321285
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发表时间：
2001-07-01
影响因子：
9.8
通讯作者：
Olek, K
中科院分区：
文献类型：
--
作者：
Leuer, M;Oldenburg, J;Olek, K
凝血因子VIII（FVIII）大基因突变是导致严重人类出血性疾病的最常见事件。在该基因中观察到的高比例的从头突变提高了这样的可能性，即显著比例的此类突变不是来自单个生殖细胞，而是应该归因于起源于早期胚胎发生期间的突变的种系或体细胞嵌合体。本研究通过使用等位基因特异性PCR分析61个家族来探讨这一假设，这些家族包括具有散发性重度血友病A和已知FVIII基因缺陷的成员。在61个家系中，有8个家系（13%）存在不同程度的体细胞嵌合现象（0.2%-25%），并已通过突变富集程序得到证实。所有嵌合体均发现于点突变家族（32个家族中的8个[25%]）。在8个具有CpG转换的家族的亚组中，具有嵌合体的百分比增加到50%（8个家族中的4个）。相反，在13个小缺失/插入或16个内含子22倒位的家庭中没有观察到嵌合体。我们的数据表明镶嵌现象可能代表血友病A中相当常见的事件。因此，在遗传咨询的风险评估应包括考虑体细胞嵌合体的可能性，在家庭显然是从头突变，特别是家庭的点突变亚型。
Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.