Combined Use of DNA Probes in First-Trimester Prenatal Diagnosis of Hemophilia A

Summary

First-trimester prenatal diagnoses of hemophilia A were heretofore obtained by using either intragenic factor VIII markers or linked cxtragcnic polymorphic markers. Postulating that the combined use of all the available intragenic and extragenic markers can render such diagnoses more frequently feasible and more reliable, we carried out ten first-trimester prenatal diagnoses in male fetuses at risk for hemophilia A by DNA analysis of chorionic villus employing in combination the intragenic Bcl I polymorphism and the St 14 (DXS 52) or DX 13 (DXS 15) extragenic probes. A diagnosis of hemophilia was obtained in three fetuses, with a diagnosis of normal fetus obtained in the remaining seven. Seven diagnoses are confirmed by factor VIII assays carried out at the time of abortion, in the mid-Trimester or at birth. A factor VIII probe recognizing Bcl I polymorphism was useful in 4 of 6 diagnoses; St 14, in 5 of 6; and DX 13 in 3 of 5. In two cases, St 14 was the only useful probe for diagnosis. Even though no recombination between extragenic probes and factor VIII gene was detected in this study, when only extragenic markers were informative we advised diagnostic confirmation on fetal plasma obtained by fetoscopy. Hence, first-trimester prenatal diagnosis of hemophilia A is feasible for the great majority of fetuses at risk through combined use of all the available intragenic and extragenic probes, providing key family members are available.

Keywords

Hemophilia A - Prenatal diagnosis - DNA analysis - Linkage analysis

• References

• 1 Mibashan RS, Rodeck CH, Thumpston JK. Plasma assay of fetal factor VIIIc and IX for prenatal diagnosis of hemophilia. Lancet 1979; 1: 1309-1311
• 2 Simoni G, Brambati B, Danesino C, Rossella F, Terzoli GL, Ferrari M, Fraccaro M. Efficient direct chromosome analysis and enzyme determination from chorionic villi samples in the first trimester of pregnancy. Human Genetics 1983; 63: 349-357
• 3 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM. Characterization of the human factor VIII gene. Nature 1984; 312: 326-330
• 4 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buccher JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC, Amphlett GW, Foster WB, Coe ML, Knudson GJ, Fass DN, Hewick RM. Molecular cloning of a cDNA encoding human antihemophilic factor. Nature 1984; 312: 342-347
• 5 Gitschier J, Drayna D, Tuddenham E GD, White RL, Lawn RM. Genetic mapping and diagnosis of hemophilia A achieved through a Bel I polymorphism in the factor VIII gene. Nature 1985; 314: 738-740
• 6 Gitschier J, Lawn RM, Rotblat F, Goldman E, Tuddenham E GD. Antenatal diagnosis and carrier detection of hemophilia A using a factor VIII gene probe. Lancet 1985; 1: 1093-1094
• 7 Antonorakis SE, Waber PG, Kittur SD, Patel AS, Kazazian HH, Mellis MA, Counts RB, Stamatoyannopoulos G, Bowie E JW, Fass DN, Pittman DD, Worzney JM, Toole JJ, Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med 1985; 313: 842-848
• 8 Wion KL, Tuddenham E GD, Lawn RM. A new polymorphism in the factor VIII gene for prenatal diagnosis of hemophilia A. Nucl Res 1986; 14: 4535-4536
• 9 Oberle L, Drayna D, Camerino G, White R, Mandel JL. The telomeric region of the human X chromosome long arm: presence of a highly polymorphic DNA marker and analysis of recombination frequency. Acad Sci USA 1985; 82: 2824-2828
• 10 Oberle L, Camerino G, Heilig R, Grunebaum L, Cazenave JP, Crapanzano C, Mannucci PM, Mandel JL. Genetic screening for hemophilia A with a polymorphic DNA probe. N Engl J Med 1985; 312: 682-686
• 11 Harper K, Winter RM, Pembrev ME, Hartley D, Davies KE, Tuddenham E GD. A clinically useful DNA probe closely linked to hemophilia A. Lancet 1984; 2: 6-8
• 12 Winter RM, Harper K, Goldman E, Mibashan RS, Warren RC, Rodeck CH, Penketh R JA, Ward P HT, Pembrev ME. First trimester prenatal diagnosis and detection of carriers of hemophilia A using the linked DNA probe DX 13. Brit Med J 1985; 291: 765-769
• 13 Peake IR, Lillicrap DP, Liadel MB, Matthews RJ, Bloom AL. Linked and intragenic probes for hemophilia A. Lancet 1985; 2: 1003-1004
• 14 Lehesjoki AE, De La Chapelle A. Rasi V: Hemophilia A: two recombinations detected with probe St 14. Lancet 1986; 2: 280
• 15 Driscoll MC, Miller CH, Goldberg JD, Aledort LM, Hoyer LW, Golbus MS. Recombination between factor VIII :C gene and St 14 locus. Lancet 1986; 2: 279
• 16 Antonorakis SE, Carpenter RJ, Hoyer LW, Toole JJ, Copeland KL, Carta CA, Caskey CT, Kazazian HH. Prenatal diagnosis of hemophilia A by factor VIII gene analysis. Lancet 1985; 1: 1407-1409
• 17 Din N, Schwartz M, Kruze T, Vestergaard SR, Ahrens P, Caput D, Hartog K, Quiroga M. Factor VIII gene specific probe for prenatal diagnosis of hemophilia A. Lancet 1985; 1: 1446-1447
• 18 Janco RL, Phillips III JA, Orlando P, Davies KE, Old J, Antonorakis SE. Carrier testing strategy in hemophilia A. Lancet 1986; 1: 148-149
• 19 Grunebaum L, Cazenave JP, Camerino G, Kloepfer C, Mandel JL, Tolstoshev P, Jaye M, De la Salle H, Lecoq JP. Carrier detection of hemophilia B by using a restriction site polymorphism associated with the coagulation factor IX gene. J Clin Invest 1984; 73: 1491-1495
• 20 Southern E. Detection of specific sequence among DNA fragments separated by gel electrophoresis. J Mol Biol 1975; 98: 503-517
• 21 Ruggeri ZM, Mannucci PM, Jeffcoate SC, Ingram G IC. Immunoradiometric assay of factor VIII related antigen with observations in 32 patients with von Willebrand’s disease. Br J Haematol 1976; 33: 221-232
• 22 Tripodi A, Mannucci PM. Factor VIII activity as measured by an amidolytic assay compared with one-stage clotting assay. Am J Clin Path 1986; 86: 341-344
• 23 Gitschier J, Wood WI, Tuddenham E G D, Shuman MA, Goralka TM, Chen EY, Lawn RM. Detection and sequence of mutations in the factor VIII gene of hemophiliacs. Nature 1985; 315: 427-430
• 24 Gitschier J, Wood WI, Shuman MA, Lawn RM. Identification of a missense mutation in the factor VIII gene of a mild hemophiliac. Science 1986; 232: 1415-1416