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Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis

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Summary

A hereditary disease with excess mortality such as haemophilia is maintained in the population by the occurrence of new cases, i.e. mutations. In haemophilia, mutations may arise in female or male ancestors of a ‘new’ patient. The ratio of the mutation frequencies in males over females determines the prior risk of carriership of the mother of an isolated patient. An estimate of this prior risk is required for the application of Bayes' theorem to probability calculations in carriership testing. We have developed a method to estimate the sex ratio of the mutation frequencies; it does not depend on the assumption of genetic equilibrium, nor require an estimate of the reproductive fitness of haemophilia patients and carriers. Information from 462 patients with severe or moderately severe haemophilia A was gathered by postal questionnaires in a survey that included practically all Dutch haemophiliacs. Pedigree analysis was performed for the 189 patients of these 462, who were the first haemophiliacs in their family. By the maximum likelihood method, the ratio of the mutation frequencies in males and females was estimated at 2.1, with a 95% confidence interval of 0.7–6.7. In addition, we performed a meta-analysis of all published studies on the sex ratio of the mutation frequencies. When the results of six studies were pooled, it was estimated that mutations originated 3.1 times as often in males as in females. The 95% confidence interval was 1.9–4.9. This implies that 80% of mothers of an isolated patient are expected to be haemophilia carriers.

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References

  • Akhmeteli MA, Aledort LM, Alexaniants S, Bulanov AL, Elston RC, Gunter EK, Goussev A, Graham JB, Hermans J, Larrieu MJ, Lothe F, McLaren AD, Manucci PM, Prentice CRM, Veltkamp JJ (1977) Methods for the detection of haemophilia carriers: a memorandum. Bull WHO 55:675–702

    Google Scholar 

  • Ananthakrishnan R, D'Souza S (1979) Some aspects of the occurrence of new mutations in haemophilia. Hum Hered 29:90–94

    Google Scholar 

  • Andreassen M (1943) Haemophilia in Denmark. Opera ex domo biologiae hereditariae humanae (in Danish). Universitatis Hafniensis (Copenh) 6:1–168

    Google Scholar 

  • Bakker E, Broeckhoven C van, Bonten EJ, Vooren MJ van de, Veenema H, Hul W van, Ommen GJB van, Vandenberghe A, Pearson PL (1987) Germline mosaicism and Duchenne muscular dystrophy mutations. Nature 329:554–556

    Google Scholar 

  • Barraï I, Cann HM, Cavalli-Sforza LL, Barbujani G, Nicola P de (1985) Segregation analysis of hemophilia A and B. Am J Hum Genet 37:680–699

    Google Scholar 

  • Bernardi F, Marchetti G, Bertagnolo V, Faggioli L, Volinia S, Patracchini P, Bartolai S, Vannini F, Felloni L, Rossi L, Panicucci F, Conconi F (1987) RFLP analysis in families with sporadic hemophilia A: estimate of the mutation ratio in male and female gametes. Hum Genet 76:253–256

    Google Scholar 

  • Biggs R, Rizza CR (1976) The sporadic case of haemophilia A. Lancet II:431–433

    Google Scholar 

  • Birch CL (1937) Hemophilia, clinical and genetic aspects. Illinois Monogr Med Sci 1:1–151

    Google Scholar 

  • Bitter K (1964) Erhebungen zur Bestimmung der Mutationsrate für Hämophilie A und B in Hamburg. Z Menschl VererbungsKonstitutionsl 37:251–268

    Google Scholar 

  • Bröcker-Vriends AHJT, Briët E, Dreesen JCFM, Bakker E, Reitsma PH, Pannekoek H, Kamp JJP van de, Pearson PL (1990) Somatic origin of inherited haemophilia A. Hum Genet 85:288–292

    Google Scholar 

  • Ekert H (1977) Carrier studies in “Simplex families”. Thromb Haemost 38:721–723

    Google Scholar 

  • Fonio A (1954) Die erblichen und die sporadischen Bluterstämme in der Schweiz. Bull Schweiz Akad Med Wiss 10:303–421

    Google Scholar 

  • Francke U, Felsenstein J, Gartler SM, Migeon BR, Dancis J, Seegmiller JE, Bakay F, Nyhan WL (1976) The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease. Am J Hum Genet 28:123–127

    Google Scholar 

  • Francke U, Felsenstein J, Gartler SM, Nyhan WL, Seegmiller JE (1977) Answer to criticism of Morton and Lalouel. Am J Hum Genet 29:307–311

    Google Scholar 

  • Greenland S (1987) Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 9:1–30

    Google Scholar 

  • Haldane JBS (1935) The rate of spontaneous mutation of a human gene. J Genet 31:317–326

    Google Scholar 

  • Haldane JBS (1947) The mutation rate of the gene for haemophilia, and its segregation ratios in males and females. Ann Eugenet (Lond) 13:262–271

    Google Scholar 

  • Hall JG (1988) Review and hypotheses: somatic mosaicism — observations related to clinical genetics. Am J Hum Genet 45:355–363

    Google Scholar 

  • Hermann J (1966) Der Einfluß des Zeugungsalters auf die Mutationen zu Hämophilie A. Humangenetik 3:1–16

    Google Scholar 

  • Higuchi M, Kochhan L, Olek K (1988) A somatic mosaic for haemophilia A detected at the DNA level. Mol Biol Med 5:23–27

    Google Scholar 

  • Holloway SM, Smith C (1973) Equilibrium frequencies in X-linked recessive disease. Am J Hum Genet 25:388–396

    Google Scholar 

  • Hoogvliet B (1942) Genetic and clinical dissertation with respect to hemophilia and colour blindness in one family (in Dutch). Genetica 23:93–220

    Google Scholar 

  • Ikkala E, Helske T, Myllyla G, Nevanlinna HR, Pitkanen P, Rasi V (1982) Changes in the life expectancy of patients with severe haemophilia in Finland in 1930–1979. Br J Haematol 52:7–12

    Google Scholar 

  • Karel ER, Meerman GJ te, Kate LP ten (1986) On the power to detect differences between male and female mutation rates for Duchenne muscular dystrophy, using classical segregation analysis and restriction fragment length polymorphisms. Am J Hum Genet 38:827–840

    Google Scholar 

  • Kosower N, Christiansen R, Morton NE (1962) Sporadic cases of hemophilia and the question of a possible sex difference in mutation rates. Am J Hum Genet 14:159–171

    Google Scholar 

  • Lane RJM, Robinow M, Roses AD (1983) The genetic status of mothers of isolated cases of Duchenne muscular dystrophy. J Med Genet 20:1–11

    Google Scholar 

  • Larsson SA (1985) Life expectancy of Swedish haemophiliacs, 1831–1980. Br J Haematol 59:593–602

    Google Scholar 

  • Larsson SA, Nilsson IM, Blomback M (1982) Current status of Swedish hemophiliacs. Acta Med Scand 212:195–200

    Google Scholar 

  • Maddalena A, Sosnoski DM, Berry GT, Nussbaum RL (1988) Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency. N Engl J Med 15:999–1003

    Google Scholar 

  • Merskey C, MacFarlane RG (1951) The female carrier of hemophilia: a clinical and laboratory study. Lancet I:487–490

    Google Scholar 

  • Morton NE (1959) Genetic tests under incomplete ascertainment. Am J Hum Genet 11:1–16

    Google Scholar 

  • Morton NE, Chung CS (1959) Formal genetics of muscular dystrophy. Am J Hum Genet 11:360–379

    Google Scholar 

  • Moser H (1984) Review of studies on the proportion and origin of new mutants in Duchenne muscular dystrophy. In: Kate LP ten, Pearson PL, Stadhouders AM (eds) Research into the origin and treatment of muscular dystrophy. Excerpta Medica, Amsterdam, pp 41–52

    Google Scholar 

  • Murphy EA, Cramer DW, Kryscio RJ, Brown CC, Pierce ER (1974) Gonadal mosaicism and genetic counseling for X-linked recessive lethals. Am J Hum Genet 26:207–222

    Google Scholar 

  • Ratnoff OD, Jones PK (1977) The laboratory diagnosis of the carrier state for classic hemophilia. Ann Intern Med 86:521–528

    Google Scholar 

  • Rosendaal FR, Varekamp I, Smit C, Bröcker-Vriends A, Van Dijck H, Vandenbroucke JP, Hermans J, Suurmeijer TPBM, Briët E (1989) Mortality and causes of death in Dutch haemophiliacs, 1973–1986. Br J Haematol 71:71–76

    Google Scholar 

  • Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC (1987) Meta-analyses of randomized controlled trials. N Engl J Med 316:450–455

    Google Scholar 

  • Smit C, Rosendaal FR, Varekamp I, Bröcker-Vriends A, Van Dijck H, Suurmeijer TPBM, Briët E (1989) Physical condition, longevity and social performance of Dutch haemophiliacs 1972–1985. Br Med J 298:235–238

    Google Scholar 

  • Thompson JS, Thompson MW (1966) Genetics in medicine. Saunders, Philadelphia

    Google Scholar 

  • Veltkamp JJ, Drion EF, Loeliger EA (1968) Detection of the carrier state in hereditary coagulation disorders, part I. Thromb Diath Haemorrh 19:279–303

    Google Scholar 

  • Vogel F (1965) Sind die Mutationsraten für die X-chromosomal recessiven Hämophilieformen in Keimzellen von Frauen niedriger als in Keimzellen von Männern? Humangenetik 1:253–263

    Google Scholar 

  • Vogel F (1977) A probable sex difference in some mutation rates. Am J Hum Genet 29:312–319

    Google Scholar 

  • Walker AM, Martin-Moreno JM, Artalejo FR (1988) Odd man out, a graphical approach to meta-analysis. Am J Public Health 78:961–966

    Google Scholar 

  • Winter RM (1980) Estimation of male to female ratio of mutation rates from carrier-detection tests in X-linked disorders. Am J Hum Genet 32:582–588

    Google Scholar 

  • Winter RM, Tuddenham EGD, Goldman E, Matthews KB (1983) A maximum likelihood estimate of the sex ratio of mutation rates in haemophilia A. Hum Genet 64:156–159

    Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Epidemiology, University Hospital Leiden, Leiden, The Netherlands

    F. R. Rosendaal & J. P. Vandenbroucke

  2. Department of Haematology, University Hospital Leiden, Leiden, The Netherlands

    F. R. Rosendaal, C. Smit & E. Briët

  3. Clinical Genetics Centre Leiden, Leiden, The Netherlands

    A. H. J. T. Bröcker-Vriends

  4. Department of Medical Statistics, State University Leiden, Leiden, The Netherlands

    J. C. van Houwelingen

  5. Dutch Haemophilia Society (NVHP), Amsterdam, The Netherlands

    C. Smit & H. van Dijck

  6. Department of Medical Sociology, State University Groningen, Groningen, The Netherlands

    I. Varekamp & T. P. B. M. Suurmeijer

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  1. F. R. Rosendaal
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  2. A. H. J. T. Bröcker-Vriends
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  3. J. C. van Houwelingen
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  4. C. Smit
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  5. I. Varekamp
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  7. T. P. B. M. Suurmeijer
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  8. J. P. Vandenbroucke
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  9. E. Briët
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Rosendaal, F.R., Bröcker-Vriends, A.H.J.T., van Houwelingen, J.C. et al. Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis. Hum Genet 86, 139–146 (1990). https://doi.org/10.1007/BF00197695

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  • DOI: https://doi.org/10.1007/BF00197695

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