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

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

doi:10.1182/blood.v86.6.2206.bloodjournal8662206

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

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

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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 ware observed among 225 cases (≃ 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%]).

Original language	English (US)
Pages (from-to)	2206-2212
Number of pages	7
Journal	Blood
Volume	86
Issue number	6
DOIs	https://doi.org/10.1182/blood.v86.6.2206.bloodjournal8662206
State	Published - Sep 15 1995
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.v86.6.2206.bloodjournal8662206

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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., ... Inaba, H. (1995). Factor VIII gene inversions in severe hemophilia A: Results of an international consortium study. Blood, 86(6), 2206-2212. https://doi.org/10.1182/blood.v86.6.2206.bloodjournal8662206

Antonarakis, SE, Rossiter, JP, Young, M, Horst, J, De Moerloose, P, Sommer, SS, Ketterling, RP, Kazazian, HH, Négrier, C, Vinciguerra, C, Gitschier, J, Goossens, M, Girodon, E, Ghanem, N, Plassa, F, Lavergne, JM, Vidaud, M, Costa, JM, Laurian, Y, Lin, SW, Lin, SR, Shen, MC, Lillicrap, D, Taylor, SAM, Windsor, S, Valleix, SV, Nafa, K, Sultan, Y, Delpech, M, Vnencak-Jones, CL, Phillips, JA, Ljung, RCR, Koumbarelis, E, Gialeraki, A, Mandalaki, T, Jenkins, PV, Collins, PW, Pasi, KJ, Goodeve, A, Peake, I, Preston, FE, Schwartz, M, Scheibel, E, Ingerslev, J, Cooper, DN, Millar, DS, Kakkar, VV, Giannelli, F, Naylor, JA, Tizzano, EF, Baiget, M, Domenech, M, Altisent, C, Tusell, J, Beneyto, M, Lorenzo, JI, Gaucher, C, Mazurier, C, Peerlinck, K, Matthijs, G, Cassiman, JJ, Vermylen, J, Mori, PG, Acquila, M, Caprino, D & Inaba, H 1995, 'Factor VIII gene inversions in severe hemophilia A: Results of an international consortium study', Blood, vol. 86, no. 6, pp. 2206-2212. https://doi.org/10.1182/blood.v86.6.2206.bloodjournal8662206

@article{b1fdf11ac9624aedb1dba49030146a50,

title = "Factor VIII gene inversions in severe hemophilia A: Results of an international consortium study",

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 ware observed among 225 cases (≃ 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%]).",

author = "Antonarakis, {S. E.} and Rossiter, {J. P.} and M. Young and J. Horst and {De Moerloose}, P. and Sommer, {S. S.} and Ketterling, {R. P.} and Kazazian, {H. H.} and C. N{\'e}grier and C. Vinciguerra and J. Gitschier and M. Goossens and E. Girodon and N. Ghanem and F. Plassa and Lavergne, {J. M.} and M. Vidaud and Costa, {J. M.} and Y. Laurian and Lin, {S. W.} and Lin, {S. R.} and Shen, {M. C.} and D. Lillicrap and Taylor, {S. A.M.} and S. Windsor and Valleix, {S. V.} and K. Nafa and Y. Sultan and M. Delpech and Vnencak-Jones, {C. L.} and Phillips, {J. A.} and Ljung, {R. C.R.} and E. Koumbarelis and A. Gialeraki and T. Mandalaki and Jenkins, {P. V.} and Collins, {P. W.} and Pasi, {K. J.} and A. Goodeve and I. Peake and Preston, {F. E.} and M. Schwartz and E. Scheibel and J. Ingerslev and Cooper, {D. N.} and Millar, {D. S.} and Kakkar, {V. V.} and F. Giannelli and Naylor, {J. A.} and Tizzano, {E. F.} and M. Baiget and M. Domenech and C. Altisent and J. Tusell and M. Beneyto and Lorenzo, {J. I.} and C. Gaucher and C. Mazurier and K. Peerlinck and G. Matthijs and Cassiman, {J. J.} and J. Vermylen and Mori, {P. G.} and M. Acquila and D. Caprino and H. Inaba",

year = "1995",

month = sep,

day = "15",

doi = "10.1182/blood.v86.6.2206.bloodjournal8662206",

language = "English (US)",

volume = "86",

pages = "2206--2212",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "6",

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TY - JOUR

T1 - Factor VIII gene inversions in severe hemophilia A

T2 - Results of an international consortium study

AU - Antonarakis, S. E.

AU - Rossiter, J. P.

AU - Young, M.

AU - Horst, J.

AU - De Moerloose, P.

AU - Sommer, S. S.

AU - Ketterling, R. P.

AU - Kazazian, H. H.

AU - Négrier, C.

AU - Vinciguerra, C.

AU - Gitschier, J.

AU - Goossens, M.

AU - Girodon, E.

AU - Ghanem, N.

AU - Plassa, F.

AU - Lavergne, J. M.

AU - Vidaud, M.

AU - Costa, J. M.

AU - Laurian, Y.

AU - Lin, S. W.

AU - Lin, S. R.

AU - Shen, M. C.

AU - Lillicrap, D.

AU - Taylor, S. A.M.

AU - Windsor, S.

AU - Valleix, S. V.

AU - Nafa, K.

AU - Sultan, Y.

AU - Delpech, M.

AU - Vnencak-Jones, C. L.

AU - Phillips, J. A.

AU - Ljung, R. C.R.

AU - Koumbarelis, E.

AU - Gialeraki, A.

AU - Mandalaki, T.

AU - Jenkins, P. V.

AU - Collins, P. W.

AU - Pasi, K. J.

AU - Goodeve, A.

AU - Peake, I.

AU - Preston, F. E.

AU - Schwartz, M.

AU - Scheibel, E.

AU - Ingerslev, J.

AU - Cooper, D. N.

AU - Millar, D. S.

AU - Kakkar, V. V.

AU - Giannelli, F.

AU - Naylor, J. A.

AU - Tizzano, E. F.

AU - Baiget, M.

AU - Domenech, M.

AU - Altisent, C.

AU - Tusell, J.

AU - Beneyto, M.

AU - Lorenzo, J. I.

AU - Gaucher, C.

AU - Mazurier, C.

AU - Peerlinck, K.

AU - Matthijs, G.

AU - Cassiman, J. J.

AU - Vermylen, J.

AU - Mori, P. G.

AU - Acquila, M.

AU - Caprino, D.

AU - Inaba, H.

PY - 1995/9/15

Y1 - 1995/9/15

N2 - 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 ware observed among 225 cases (≃ 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%]).

AB - 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 ware observed among 225 cases (≃ 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%]).

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U2 - 10.1182/blood.v86.6.2206.bloodjournal8662206

DO - 10.1182/blood.v86.6.2206.bloodjournal8662206

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SP - 2206

EP - 2212

JO - Blood

JF - Blood

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ER -

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

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