重度甲型血友病中凝血因子VIII基因倒位：一项国际协作组研究的结果

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

作者信息

Antonarakis S E, Rossiter J P, Young M, Horst J, de Moerloose P, Sommer S S, Ketterling R P, Kazazian H H, Négrier C, Vinciguerra C, Gitschier J, Goossens M, Girodon E, Ghanem N, Plassa F, Lavergne J M, Vidaud M, Costa J M, Laurian Y, Lin S W, Lin S R, Shen M C, Lillicrap D, Taylor S A, Windsor S, Valleix S V, Nafa K, Sultan Y, Delpech M, Vnencak-Jones C L, Phillips J A, Ljung R C, Koumbarelis E, Gialeraki A, Mandalaki T, Jenkins P V, Collins P W, Pasi K J, Goodeve A, Peake I, Preston F E, Schwartz M, Scheibel E, Ingerslev J, Cooper D N, Millar D S, Kakkar V V, Giannelli F, Naylor J A, Tizzano E F, Baiget M, Domenech M, Altisent C, Tusell J, Beneyto M, Lorenzo J I, Gaucher C, Mazurier C, Peerlinck K, Matthijs G, Cassiman J J, Vermylen J, Mori P G, Acquila M, Caprino D, Inaba H

机构信息

Geneva University Medical School, Switzerland.

出版信息

Blood. 1995 Sep 15;86(6):2206-12.

PMID:7662970

Abstract

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

摘要

来自14个国家的22个分子诊断实验室参与了一项联合研究，以评估因子VIII基因倒位对重度A型血友病的影响。共研究了2093例重度A型血友病患者；其中，740例（35%）发生1型（远端）因子VIII倒位，140例（7%）表现为2型（近端）倒位。在25例中，分子分析显示出额外的异常或多态性模式。倒位患者的532名母亲中有98%是异常因子VIII基因的携带者；仅研究非家族性病例的母亲时，在225例中观察到9例母源生殖细胞中的新发倒位（散发病例的25名母亲中约有1例倒位源于母源新发）。检查母系祖父母的起源时，69例倒位发生在男性生殖细胞的新发突变，1例发生在女性生殖细胞。因子VIII倒位的存在不是因子VIII抑制剂形成的主要诱发因素；然而，重度A型血友病且有因子VIII倒位的患者发生抑制剂的比例（642例中的130例[20%]）略高于无倒位的重度A型血友病患者（821例中的131例[16%]）。