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Thromb Haemost 1987; 57(02): 131-136
DOI: 10.1055/s-0038-1651080
Original Article
Schattauer GmbH Stuttgart

Genotype Assignment of Haemophilia A by Use of Intragenic and Extragenic Restriction Fragment Length Polymorphisms

A H J T Bröcker-Vriends
1   The Clinical Genetics Centre, University Hospital, Leiden, The Netherlands
,
E Briët
2   The Department of Haematology, University Hospital, Leiden, The Netherlands
,
R Quadt
2   The Department of Haematology, University Hospital, Leiden, The Netherlands
,
J C F M Dreesen
2   The Department of Haematology, University Hospital, Leiden, The Netherlands
,
E Bakker
3   The Department of Human Genetics, University Hospital, Leiden, The Netherlands
,
R Claassen-Tegelaar
2   The Department of Haematology, University Hospital, Leiden, The Netherlands
,
H H H Kanhai
4   The Department of Obstetrics and Gynaecology, University Hospital, Leiden, The Netherlands
,
J J P van de Kamp
1   The Clinical Genetics Centre, University Hospital, Leiden, The Netherlands
,
P L Pearson
3   The Department of Human Genetics, University Hospital, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 02 October 1986

Accepted after revision 05 December 1986

Publication Date:
23 July 2018 (online)

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Summary

We performed DNA analysis in 20 families with haemophilia A in order to evaluate its usefulness for carrier detection and prenatal diagnosis.

The polymorphic Bell site within intron 18 of the factor VIII gene and the extragenic TaqI and Bglll polymorphic sites which are detected by the random DNA probes designated St 14 and DX13, respectively, were investigated for.

Two events of recombination were found between the St 14 and the haemophilia A locus in 51 informative meioses. In one of these recombinant meioses crossing over had also occurred between the DX13 and the haemophilia A locus. No further crossovers between the DX13 and the haemophilia A locus were found in 20 informative meioses.

Segregation analysis of the polymorphic markers and the deleterious mutation within the families allowed a diagnosis at the gene level for 52 out of 57 potential carriers. The new method considerably decreased the uncertainty about carriership for seventeen of the nineteen women with a probability of carriership between 5% and 95% based on pedigree analysis and factor VIII assays.

In seven cases chromosome and DNA analysis of a chorionic villus biopsy was carried out. Three of the fetuses were female, four were male. Three of the male fetuses had inherited the normal maternal X-chromosome and were, therefore, not affected. For another male fetus no diagnosis at the gene level was possible since the mother was homozygous for all the known restriction fragment length polymorphisms within or closely linked with the haemophilia A locus.

Keywords

Carrier detection - Haemophilia A - Prenatal diagnosis - Restriction fragment length polymorphisms
 

  • References

  • 1 Varekamp I, Smit C, Rosendaal F, Suurmeijer Th, Bröcker-Vriends A, Van Ingen B, Briet E. A national survey on hemophilia: data collecting by mail questionaires (abstract). Research in clinic and laboratory 1986; 16: 121
    PubMedSearch in Google Scholar
  • 2 Veltkamp JJ, Drion EF, Loeliger EA. Detection of the carrierstate in hereditary coagulation disorders II. Thromb Diathes Haemorrh 1968; 19: 403-422
    PubMedSearch in Google Scholar
  • 3 Zimmerman TS, Ratnoff OD, Littell AS. Detection of the carrier state of classic hemophilia using an immunologic assay for antihemophilic factor (factor VIII). J Clin Invest 1971; 50: 255-255
    CrossrefPubMedSearch in Google Scholar
  • 4 Elston RC, Graham JB, Miller CH, Reisner HM, Bouma BN. Probabilistic classification of hemophilia A carriers by discriminant analysis. Thromb Res 1976; 8: 683-695
    CrossrefPubMedSearch in Google Scholar
  • 5 Graham JB, Rizza CR, Chediak J, Mannucci PM, Briet E, Ljung R, Kasper CC, Essein EM, Green PP. Carrier detection in hemophilia A: a cooperative international study. I The carrier phenotype Blood 1986; 67: 1554-1559
    PubMedSearch in Google Scholar
  • 6 Green PP, Mannucci PM, Briet E, Ljung R, Kasper CC, Essein EM, Chediak J, Rizza ER, Graham JB. Carrier detection in hemophilia A: a cooperative international study. II The efficacy of a universal discriminant. Blood 1986; 67: 1560-1567
    PubMedSearch in Google Scholar
  • 7 Bouma BN, Van der Klaauw MM, Veltkamp JJ, Starkenburg AE, Van Tilburg NH, Hermans J. Evaluation of the detection rate of hemophilia carriers. Thromb Res 1975; 7: 339-350
    CrossrefPubMedSearch in Google Scholar
  • 8 Barrow ES, Miller CH, Reisner HM, Graham JB. Genetic counselling in haemophilia by discriminant analysis 1975-1980. J Med Gen 1982; 19: 26-34
    CrossrefPubMedSearch in Google Scholar
  • 9 Mibashan RS, Rodeck CH, Thumpston JK. Prenatal diagnosis of the hemophilias. In Methods in Hematology; The Hemophilias. Bloom AL. (Ed) Churchill Livingstone; Edinburgh: 1982. pp 176-197
    Search in Google Scholar
  • 10 Evans D IK, Shaw A. Attitudes of haemophilia carriers to fetoscopy and amniocentesis. Lancet 1979; ii 1371
    PubMedSearch in Google Scholar
  • 11 Antonarakis SE, Waber PG, Kittur SD, Patel AS, Kazazian HH, Mellis MA, Counts RB, Stamatoyannopoulos G, Bowie E JW, Fass DN, Pittman DD, Wozney JM, Toole JJ. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med 1985; 313: 842-848
    CrossrefPubMedSearch in Google Scholar
  • 12 Gitschier J, Wood WI, Tuddenham E GD, Shuman MA, Goralka TM, Chen EY, Lawn RM. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature 1985; 315: 427-428
    CrossrefPubMedSearch in Google Scholar
  • 13 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
    CrossrefPubMedSearch in Google Scholar
  • 14 Gitschier J, Drayna D, Tuddenham E GD, White RL, Lawn RM. Genetic mapping and diagnosis of haemophilia A achieved through a Bell polymorphism in the factor VIII gene. Nature 1985; 314: 738-740
    CrossrefPubMedSearch in Google Scholar
  • 15 Wion KL, Tuddenham E GD, Lawn RM. A new polymorphism in the factor VIII gene for prenatal diagnosis of Hemophilia A. Nucleic Acids Res 1986; 11: 4535-4542
    PubMedSearch in Google Scholar
  • 16 Harper K, Pembrey ME, Davies KE, Winter RM, Hartley D, Tuddenham E GD. A clinically useful DNA probe closely linked haemophilia A. Lancet 1984; ii 6-8
    PubMedSearch in Google Scholar
  • 17 Oberle I, Camerino G, Heilig R, Grunebaum L, Cazenave JJ, Crapanzano C, Mannucci PM, Mandel JL. Genetic screening for hemophilia A (classic hemophilia) with a polymorphic DNA probe. N Engl J Med 1985; 682-686
    PubMedSearch in Google Scholar
  • 18 Veltkamp JJ, Drion EF, Loeliger EA. Detection of the carrier state in hereditary coagulation disorders I. Thromb Diathes Haemorrh 1968; 19: 279-303
    PubMedSearch in Google Scholar
  • 19 Laurell CB. Quantitative estimation of protein by electrophoresis in agarose gels containing antibodies. Analyt Biochem 1966; 15: 45-52
    CrossrefPubMedSearch in Google Scholar
  • 20 Weening RS, Roos D, Loos JA. Oxygen consumption of phagocytising cells in human leucocyte and granulocyte preparations: a comparative study. J Lab Clin Med 1974; 83: 570-576
    PubMedSearch in Google Scholar
  • 21 Baas F, Bikker H, Van Ommen G-JB, De Vijlder J JM. Unusual scarcity of restriction sites in the human thyroglobulin gene. A linkage study suggesting autosomal dominance of a defective thyroglobulin allele. Hum Genet 1984; 67: 301-305
    CrossrefPubMedSearch in Google Scholar
  • 22 Hofker MH, Wapenaar MC, Goor N, Bakker B, Van Ommen G-JB, Pearson PL. Isolation of probes detecting restriction fragment length polymorphisms from X chromosome specific libraries: Potential use for diagnosis of Duchenne muscular dystrophy. Hum Genet 1985; 70: 148-156
    CrossrefPubMedSearch in Google Scholar
  • 23 Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 1975; 98: 503-517
    CrossrefPubMedSearch in Google Scholar
  • 24 Goodfellow PN, Davies KE, Ropers HH. Report of the committee on the genetic constitution of the X and Y chromosomes. Human Gene Mapping 8. Cytogenetics and cellgenetics 1980; 40: 296-352
    PubMedSearch in Google Scholar
  • 25 Bröcker-Vriends A HJ T, Briet E, Quadt R, Bertina RM, Van der Linden IK, Van de Kamp J JP, Pearson PL, Veltkamp JJ. Carrier detection of Haemophilia B by using an intragenic restriction fragment length polymorphism. Thromb Haemostas 1985; 54: 506-509
    PubMedSearch in Google Scholar
  • 26 Akhmeteli MA, Aledort LN, Alexiantes S. Methods for the detection of haemophilia carriers: a memorandum. Bull WHO 1977; 55: 675-702
    PubMedSearch in Google Scholar
  • 27 Hoyer LW, Carta CA, Mahoney MJ. Detection of Hemophilia carriers during pregnancy. Blood 1982; 60: 6
    PubMedSearch in Google Scholar
  • 28 Mibashan RS, Peake IR, Newcombe RG, Thumpston JK, Gorer R, Furlong RA, Rodeck CH. tCarrier detection of haemophilia A in pregnancy by measurement of factor VIII:C/RAg and VIII:CAg/RAg ratios. Thromb Haemostas 1981; 46: 187 (Abstr)
    PubMedSearch in Google Scholar
  • 29 Graham JB, Barrow ES, Flyer P, Dawson DV, Elston RC. Identifying Carriers of Mild Haemophilia. Brit J Haem 1980; 44: 671-678
    CrossrefPubMedSearch in Google Scholar
  • 30 Miller DH, Hilgartner MW, Harris MB, Bussel JB, Aledort LM. Concurrence of Von Willebrand’s Disease and Hemophilia A: Implications for Carrier Detection and Prevalence. Am J Med Gen 1986; 24: 83-94
    CrossrefPubMedSearch in Google Scholar
  • 31 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 1985; 312: 326-330
    PubMedSearch in Google Scholar
  • 32 Janco RL, Philips JA, Orlando P, Davies KE, Old J, Antonarakis SE. Carrier testing strategy in Haemophilia A. Lancet 1986; i 148-149
    PubMedSearch in Google Scholar
  • 33 Peake I, Lillicrap DP, Liddel MB, Matthews RJ, Bloom AL. Linked and intragenic probes for haemophilia A. Lancet 1985; ii 1003-1004
    PubMedSearch in Google Scholar
  • 34 Winter RM, Harper K, Goldman E, Mibashan RR, Warren RC, Rodeck CH, Penketh R JA, Ward R HT, Hardisty RM, Pembrey ME. First trimester prenatal diagnosis and detection of carriers of haemophilia A using the linked DNA probe DX13. Brit Med J 1985; 291: 765-769
    CrossrefPubMedSearch in Google Scholar
  • 35 Vidaud M, Oberle I, Mandel JL, Goossens M. DNA polymorphisms in hemophilia A (abstract). Research in clinic and laboratory 1986; 16: 182
    PubMedSearch in Google Scholar
  • 36 Pecorara M, Mori PG, Casarino L, Morfini M, Mancuso G, De Biasi R, Rippa T, Boeri E, Loi A, Perseu L, Cao A, Pirastu M. Hemophilia A: carrier detection and prenatal diagnosis by DNA analysis (abstract). Research in clinic and laboratory 1986; 16: 183
    PubMedSearch in Google Scholar
  • 37 Driscoll C, Miller CH, Goldberg JD, Aledort LM, Hoyer LW, Golbus MS. Recombination between factor VIII:C gene and St14 locus. Lancet 1986; ii 279
    PubMedSearch in Google Scholar
  • 38 Lehesjoki AE, De la Chapelle A, Rasi V. Haemophilia A: two recombinations detected with probe St14. Lancet 1986; ii 280
    PubMedSearch in Google Scholar
  • 39 Peake IR, Bloom AL. Recombination between genes and closely linked polymorphisms. Lancet 1986; i 1335-1336
    PubMedSearch in Google Scholar
  • 40 Oberle I, 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. Proc Natl Acad Sci 1985; 82: 2824-2828
    CrossrefPubMedSearch in Google Scholar
  • 41 Kerr CB. Genetics of Human Blood Coagulation. J Med Genet 1965; 2: 221-308
    CrossrefPubMedSearch in Google Scholar