Direct and indirect estimation of the sex ratio of mutation frequencies in hemophilia A

Carrier detection tests were carried out in 119 families with hemophilia A by using the data obtained with current DNA techniques (e.g., RFLP analysis and direct identification of mutations), conventional carrier detection tests (e.g., factor VIII:C and von Willebrand factor antigen), and pedigree i...

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Bibliographic Details
Published in:American journal of human genetics 1993-12, Vol.53 (6), p.1229-1238
Main Authors: Oldenburg, J, Schwaab, R, Grimm, T, Zerres, K, Hakenberg, P, Brackmann, H H, Olek, K
Format: Article
Language:English
Subjects:
Adolescent
Adult
Child
Child, Preschool
factor VIII deficiency
Female
frequency
Gene Frequency
Genetic Carrier Screening
Germany - epidemiology
Hemophilia A - epidemiology
Hemophilia A - genetics
Heterozygote
Humans
Infant
Male
man
Mathematics
Middle Aged
Mutation
Polymorphism, Restriction Fragment Length
Probability
Regression Analysis
Risk Factors
Sex Ratio
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Summary:Carrier detection tests were carried out in 119 families with hemophilia A by using the data obtained with current DNA techniques (e.g., RFLP analysis and direct identification of mutations), conventional carrier detection tests (e.g., factor VIII:C and von Willebrand factor antigen), and pedigree information. On the basis of this data, we estimated the sex ratio of mutation frequencies with three completely different methods and compared the results. Since the classical indirect method derived from Haldane is substantially influenced by reproductive fitness (f), the sex ratio of mutation frequencies was estimated for both f = .3 and f = .5, resulting in a male:female mutation ratio of 5.37 (95% confidence interval 2.16-13.02) and 3.26 (95% confidence interval 0.97-8.73), respectively. According to the equilibrium-independent indirect method formulated by Rosendaal et al., the male:female ratio was estimated to be 3.4 (95% confidence interval 1.18-8.81). Since current DNA techniques provide information on the grandparental origin of the patient's X chromosome, we were twice able to estimate directly the male:female mutation ratio as 15:1, by using the quotients of mutation origin (maternal grandfather/maternal grandmother and maternal grandfather/patient's mother, respectively). Application of the Fisher test shows that the male mutation rate is higher than the female rate (P = 8.55 x 10(-7). Since all three completely different approaches unequivocally showed a higher male than female mutation frequency, this should be considered to be an established fact in calculating the risk in hemophilia A families.
ISSN:0002-9297
1537-6605