Weinmann A F, Schoof J M, Thompson A R
Department of Medicine and Pediatrics, University of Washington, Seattle, USA.
Am J Hematol. 1996 Mar;51(3):192-9. doi: 10.1002/(SICI)1096-8652(199603)51:3<192::AID-AJH3>3.0.CO;2-S.
Inversions between a gene A copy within intron 22 of the factor VIII gene and additional copies outside the factor VIII gene were found in 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy in 14, and a third (variant) copy in one. Baseline factor VIII clotting levels were <1% of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had < or = 1% activity levels nor in 42 families with moderately severe hemophilia A and 2-5% baseline levels. Both high titer and low level alloantibody inhibitors were found in patients with of without an inversion. Of 13 high titer inhibitors, 8 were persistent and 1 of these patients had an inversion. Of 5 that responded to daily factor VIII infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilia was isolated in 30 and the mother was a carrier in the 25 in which additional family members were informative. In three of these families with isolated occurrence, the maternal grandmother was a carrier whereas in three others a de novo mutation occurred in the maternal grandfather's factor VIII gene. Screening for gene inversions in patients with severe (or "borderline" severe) hemophilia A provides a direct marker of the mutation in 45% of families. It is useful even if there is no living affected member and in predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A.
在49个甲型血友病家庭中，发现因子VIII基因内含子22内的一个基因A拷贝与因子VIII基因外的其他拷贝之间存在倒位。倒位模式为：与远端基因A拷贝重组的有34个家庭，与近端拷贝重组的有14个家庭，与第三个（变异）拷贝重组的有1个家庭。43个家庭的基线因子VIII凝血水平<正常水平的1%，6个家庭为1%。在另外61个受影响成员活性水平≤1%的家庭以及42个中度严重甲型血友病且基线水平为2 - 5%的家庭中未检测到倒位。无论有无倒位，患者中均发现了高滴度和低水平的同种异体抗体抑制剂。在13个高滴度抑制剂患者中，8个是持续性的，其中1例患者存在倒位。在5个对每日因子VIII输注有反应的患者中，4个患者存在基因倒位。在49个有倒位的家庭中，30个家庭的血友病为散发性，在另外25个有更多家庭成员信息的家庭中，母亲为携带者。在其中3个散发性家庭中，外祖母为携带者，而在另外3个家庭中，外祖父的因子VIII基因发生了新发突变。对重度（或“临界重度”）甲型血友病患者进行基因倒位筛查，可为45%的家庭提供突变的直接标志物。即使没有在世的受影响成员，它也很有用，并且可用于预测没有可靠基线凝血活性的婴儿的可能严重程度，包括70%的散发性甲型血友病家庭。
