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. 1982 Feb;19(1):26–34. doi: 10.1136/jmg.19.1.26

Genetic counselling in haemophilia by discriminant analysis 1975-1980*

Emily S Barrow †, Connie H Miller ‡, Howard M Reisner †, John B Graham †
PMCID: PMC1048815  PMID: 7069742

Abstract

Between January 1975 and January 1980 we counselled 214 possible or obligatory carriers of haemophilia A in an attempt to provide the counsel they needed and to determine the utility of a probabilistic method of assigning the heterozygous genotype (carrier detection). We found the method of assignment to be quick and easy to use, and the single output (the final probability favouring carriership P(C)) to be understood by most counsellees. The final probabilities obtained were either very high or very low in 80% of the women, which allowed us to give clear counsel in four instances in five. The final probabilities could also be used to relate Mendelian expectation to observation within each of three subsets of women (18 mothers of sporadic haemophiliacs, 78 sisters, and 62 more distant relatives), while the aberrant likelihood ratios of 6/36 (17%) of the obligatory carriers provided an estimate of the false negative diagnostic rate owing to lyonisation. There was no significant age effect on VIII:C or VIIIR:Ag levels of obligatory carriers, and the VIII:C levels of the obligatory carriers who had received the gene from their fathers did not differ from those of the obligatory carriers who had received the gene from their mothers. The ratios of high:low probabilities among the sisters and distant relatives of haemophiliacs conformed to genetic expectation, while the ratio among mothers of sporadic haemophiliacs suggested that their expectations of carriership were greater than 80%.

Twenty of the 214 counsellees (9%) were pregnant on the first visit, and 13 of those with low P(C)s (0·0-0·33) went to term and delivered 11 non-haemophilic children. Four with P(C)s between 0·50 and 1·00 requested amniocenteses, and one male was aborted. Three who were obligatory carriers also requested amniocentesis which led to the abortion of a second male.

Seven women who were assessed before pregnancy and found to have high P(C)s returned after becoming pregnant. All requested amniocentesis (one twice) and fetoscopy was requested for six of the seven males discovered, one male having been aborted before fetoscopy became available. Of the six males who were fetoscoped, three normal males reached term, one normal male was born prematurely, and one haemophilic male and one normal male did not survive fetoscopy.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett B., Ratnoff O. D. Detection of the carrier state for classic hemophilia. N Engl J Med. 1973 Feb 15;288(7):342–345. doi: 10.1056/NEJM197302152880704. [DOI] [PubMed] [Google Scholar]
  2. Bennett E., Huehns E. R. Immunological differentiation of three types of haemophilia and identification of some female carriers. Lancet. 1970 Nov 7;2(7680):956–958. doi: 10.1016/s0140-6736(70)92129-x. [DOI] [PubMed] [Google Scholar]
  3. Biggs R., Rizza C. R. The sporadic case of haemophilia A. Lancet. 1976 Aug 28;2(7983):431–433. doi: 10.1016/s0140-6736(76)92523-x. [DOI] [PubMed] [Google Scholar]
  4. Bouma B. N., van der Klaauw M. M., Veltkamp J. J., Starkenburg A. E., van Tilburg N. H., Hermans J. Evaluation of the detection rate of hemophilia carriers. Thromb Res. 1975 Aug;7(2):339–350. doi: 10.1016/0049-3848(75)90192-9. [DOI] [PubMed] [Google Scholar]
  5. Chediak J., Telfer M. C., Jaojaroenkul T., Green D. Lower factor VIII coagulant in daughters of subjects with hemophilia A compared to other obligate carriers. Blood. 1980 Apr;55(4):552–558. [PubMed] [Google Scholar]
  6. Denson K. W. The detection of factor-VIII-like antigen in haemophilic carriers and in patients with raised levels of biologically active factor VIII. Br J Haematol. 1973 Apr;24(4):451–461. doi: 10.1111/j.1365-2141.1973.tb01671.x. [DOI] [PubMed] [Google Scholar]
  7. Ekert H., Helliger H., Muntz R. H. Detection of carriers of haemophilia. Thromb Diath Haemorrh. 1973 Nov;30(2):255–262. [PubMed] [Google Scholar]
  8. Ekert H., Helliger H., Muntz R. H. Detection of carriers of haemophilia. Thromb Diath Haemorrh. 1973 Nov;30(2):255–262. [PubMed] [Google Scholar]
  9. Elston R. C., Graham J. B., Miller C. H., Reisner H. M., Bouma B. N. Probabilistic classification of hemophilia A carriers by discriminant analysis. Thromb Res. 1976 May;8(5):683–695. doi: 10.1016/0049-3848(76)90248-6. [DOI] [PubMed] [Google Scholar]
  10. Evans D. I., Shaw A. Attitudes of Haemophilia carrier to fetoscopy and amniocentesis. Lancet. 1979 Dec 22;2(8156-8157):1371–1371. doi: 10.1016/s0140-6736(79)92856-3. [DOI] [PubMed] [Google Scholar]
  11. Factor VIII in hemophilia. Blood. 1980 Oct;56(4):742–743. [PubMed] [Google Scholar]
  12. Factor VIII in hemophilia. Blood. 1980 Oct;56(4):742–743. [PubMed] [Google Scholar]
  13. Firshein S. I., Hoyer L. W., Lazarchick J., Forget B. G., Hobbins J. C., Clyne L. P., Pitlick F. A., Muir W. A., Merkatz I. R., Mahoney M. J. Prenatal diagnosis of classic hemophilia. N Engl J Med. 1979 Apr 26;300(17):937–941. doi: 10.1056/NEJM197904263001701. [DOI] [PubMed] [Google Scholar]
  14. Francke U., Felsenstein J., Gartler S. M., Migeon B. R., Dancis J., Seegmiller J. E., Bakay F., Nyhan W. L. The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease. Am J Hum Genet. 1976 Mar;28(2):123–137. [PMC free article] [PubMed] [Google Scholar]
  15. Graham J. B., Barrow E. S., Elston R. C. Lyonization in hemophilia: a cause of error in direct detection of heterozygous carriers. Ann N Y Acad Sci. 1975 Jan 20;240:141–146. doi: 10.1111/j.1749-6632.1975.tb53335.x. [DOI] [PubMed] [Google Scholar]
  16. Graham J. B., Barrow E. S., Flyer P., Dawson D. V., Elston R. C. Identifying carriers of mild haemophilia. Br J Haematol. 1980 Apr;44(4):671–678. doi: 10.1111/j.1365-2141.1980.tb08721.x. [DOI] [PubMed] [Google Scholar]
  17. Graham J. B. Genotype assignment (carrier detection) in the haemophilias. Clin Haematol. 1979 Feb;8(1):115–145. [PubMed] [Google Scholar]
  18. Graham J. B., Miller C. H., Reisner H. M., Elston R. C., Olive J. A. The phenotypic range of hemophilia A carriers. Am J Hum Genet. 1976 Sep;28(5):482–488. [PMC free article] [PubMed] [Google Scholar]
  19. Karp L. E. Genetic drift: genetic screening. Am J Med Genet. 1980;5(1):1–3. doi: 10.1002/ajmg.1320050102. [DOI] [PubMed] [Google Scholar]
  20. Klein H. G., Aledort L. M., Bouma B. N., Hoyer L. W., Zimmerman T. S., DeMets D. L. A co-operative study for the detection of the carrier state of classic hemophilia. N Engl J Med. 1977 Apr 28;296(17):959–962. doi: 10.1056/NEJM197704282961702. [DOI] [PubMed] [Google Scholar]
  21. Methods for the detection of haemophilia carriers: a memorandum. Bull World Health Organ. 1977;55(6):675–702. [PMC free article] [PubMed] [Google Scholar]
  22. Meyer D., Plas A., Allain J. P., Sitar G. M., Larrieu M. J. Problems in the detection of carriers of haemophilia A. J Clin Pathol. 1975 Sep;28(9):690–695. doi: 10.1136/jcp.28.9.690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mibashan R. S., Rodeck C. H., Thumpston J. K., Edwards R. J., Singer J. D., White J. M., Campbell S. Plasma assay of fetal factors VIIIC and IX for prenatal diagnosis of haemophilia. Lancet. 1979 Jun 23;1(8130):1309–1311. doi: 10.1016/s0140-6736(79)91946-9. [DOI] [PubMed] [Google Scholar]
  24. Morgan T. H. SEX LIMITED INHERITANCE IN DROSOPHILA. Science. 1910 Jul 22;32(812):120–122. doi: 10.1126/science.32.812.120. [DOI] [PubMed] [Google Scholar]
  25. Morton N. E., Lalouel J. M. Genetic counseling in sex linkage. Birth Defects Orig Artic Ser. 1979;15(5C):9–24. [PubMed] [Google Scholar]
  26. Prentice C. R., Forbes C. D., Morrice S., McLaren A. D. Calculation of predictive odds for possible carriers of heamophilia. Thromb Diath Haemorrh. 1975 Dec 15;34(3):740–747. [PubMed] [Google Scholar]
  27. Ratnoff O. D., Jones P. K. The laboratory diagnosis of the carrier state for classic hemophilia. Ann Intern Med. 1977 May;86(5):521–528. doi: 10.7326/0003-4819-86-5-521. [DOI] [PubMed] [Google Scholar]
  28. Reisner H. M., Katz H. J., Goldin L. R., Barrow E. S., Graham J. B. Use of a simple visual assay of Willebrand factor for diagnosis and carrier identification. Br J Haematol. 1978 Oct;40(2):339–350. doi: 10.1111/j.1365-2141.1978.tb03669.x. [DOI] [PubMed] [Google Scholar]
  29. Rizza C. R., Rhymes I. L., Austen D. E., Kernoff P. B., Aroni S. A. Detection of carriers of haemophilia: a 'blind' study. Br J Haematol. 1975 Aug;30(4):447–456. doi: 10.1111/j.1365-2141.1975.tb01859.x. [DOI] [PubMed] [Google Scholar]
  30. Roses A. D., Roses M. J., Miller S. E., Hull K. L., Jr, Appel S. H. Carrier detection in Duchenne muscular dystrophy. N Engl J Med. 1976 Jan 22;294(4):193–198. doi: 10.1056/NEJM197601222940404. [DOI] [PubMed] [Google Scholar]
  31. Rubin R., Niemetz J., Estren S. Use of animal AHG concentrates (factor VIII) in the treatment of life-threatening hemorrhage in patients with factor VIII antibodies. Ann N Y Acad Sci. 1975 Jan 20;240:362–369. doi: 10.1111/j.1749-6632.1975.tb53375.x. [DOI] [PubMed] [Google Scholar]
  32. Veltkamp J. J., Drion E. F., Loeliger E. A. Detection of the carrier state in hereditary coagulation disorders. II. Thromb Diath Haemorrh. 1968 Jul 31;19(3):403–422. [PubMed] [Google Scholar]
  33. Zimmerman T. S., Ratnoff O. D., Littell A. S. Detection of carriers of classic hemophilia using an immunologic assay for antihemophilic factor (factor 8(). J Clin Invest. 1971 Jan;50(1):255–258. doi: 10.1172/JCI106481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zimmerman T. S., Ratnoff O. D., Powell A. E. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand's dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor. J Clin Invest. 1971 Jan;50(1):244–254. doi: 10.1172/JCI106480. [DOI] [PMC free article] [PubMed] [Google Scholar]

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