Carrier detection in hemophilia A: a cooperative international study. II. The efficacy of a universal discriminant

Green, PP; Pm, Mannucci; Briet, E; Ljung, R; Kasper, CK; Essien, E M; Chediak, J; Rizza, CR; Jb, Graham

doi:10.1182/blood.v67.6.1560.bloodjournal6761560

Cited by 7 publications

(10 citation statements)

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“…It was concluded that in these 10 families a mutation had occurred either in the grandfather's or mother's germ cell. To ascertain in which generation the mutation had occurred, VIII : C and vWF concentrations were determined in the mothers of the hemophiliacs in these 10 families, and the odds on maternal carriership estimated by linear discriminant analysis (16). Of these 10 mothers, four had odds of > 104: 1 for carriership, two for non-carriership (odds t0.025: I), i.e., the mutation had probably occurred in the mother's germ cell, and four were indeterminate.…”

Section: Resultsmentioning

confidence: 99%

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More Than Half the Sporadic Cases of Hemophilia A in Sweden Are Due to a Recent Mutation

Ljung

Kling

Sjörin³

et al. 1991

Acta Paediatrica

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The aim of this study was to ascertain how many of the sporadic cases of severe Haemophilia A in Sweden are due to recent mutation, and establish its origin. DNA analysis was performed in 18 randomly selected families with a sporadic case of severe haemophilia A. Restriction fragment length polymorphism (RFLP) patterns were investigated, two intragenic (Bc1 I, Xba I/Kpn I) and two extragenic (DX 13, St 14) RFLP being used. In 10/18 families a haemophilia-linked gene was found to have derived from the healthy maternal grandfather; on the basis of clotting and immunological assay results, the odds were high (greater than 104:1) for maternal carriership in four of these 10 cases, and for maternal non-carriership in two, four being indeterminate. In 4/18 families a haemophilia-linked gene derived from the healthy maternal grandmother; according to clotting and immunological assay results, in two cases the odds were high for maternal non-carriership. In the remaining 4/18 families no conclusions could be drawn from the RFLP pattern as to the origin of mutation. We conclude that at least 55% of the sporadic cases of severe hemophilia A in Sweden are due to a recent mutation within the last two generations.

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Section: Resultsmentioning

confidence: 99%

“…St 14 (kindly provided by Dr J.-L. Mandel, Inserm, Strasbourg), which after digestion with Taq 1 detects an extragenic polymorphic system with 10 alleles (1 1).Statistics. The odds for carriership based on concentrations of VII1:C and wWF were estimated with linear discriminant analysis as perGreen et al (1986).…”

mentioning

confidence: 99%

More Than Half the Sporadic Cases of Hemophilia A in Sweden Are Due to a Recent Mutation

Ljung

Kling

Sjörin³

et al. 1991

Acta Paediatrica

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“…5 Accuracy in the assessment of the probability of carriership can be enhanced by using a program for computer analysis of data for laboratory variables. 6 The combined use of pedigree and laboratory data will only yield a probability of carriership, even if it is often very strong.…”

Section: Basic Analysis Of the Potential Carriermentioning

confidence: 99%

Genetic Counseling of Hemophilia Carriers

Ljung¹,

Tedgård²

2003

Semin Thromb Hemost

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Basic analysis of a potential carrier includes calculation of the probability, or odds, for carriership based on pedigree and clotting factor analysis. Genotype assessment constitutes a more accurate method of carrier detection. Where circumstances permit, the genetic diagnosis of hemophilia should be based on the direct identification of the pathogenic mutation in the factor (F) VIII gene. Neutral mutations in the FVIII gene and the risk of mosaicism (a mixture of normal and mutation carrying cells) in sporadic families may cause misclassification. If it is not possible to use the mutation for diagnostic purposes, it may be possible to use linked polymorphic markers (restriction fragment length polymorphisms [RFLP]) to trace the inheritance of the hemophilia gene within a pedigree. Linkage analysis is limited because of uninformative patterns of polymorphic markers, ethnic variation, linkage disequilibrium, and the need for participation of family members, and it is not useful in sporadic families, which constitute more than half of the hemophilia families. Potential carriers of hemophilia should be offered qualified assistance in genetic information, testing, and counseling to help them to cope with the psychological and ethical problems related to carriership of a genetic disorder.

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“…Nevertheless, between 6 and 20% of women will be misclassified either as normal or as carriers on the basis of these methods. 11,15,[21][22][23] A complementary and highly reliable method for this task has been provided by recombinant DNA technology.…”

Section: Genetics Of Hemophilia Amentioning

confidence: 99%

Recombinant DNA Methods in Hemophilia A: Carrier Detection and Prenatal Diagnosis*

Sadler

1990

Semin Thromb Hemost

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Hemophilia A is a serious inherited bleeding disorder of man that is caused by deficiency of blood coagulation Factor VIII. Major clinical problems in the treatment of hemophilia A include the transmission of disease by therapeutic blood products and the development of alloantibody inhibitors to transfused Factor VIII. The genetic counseling of affected families is made more difficult by the inherent inaccuracy of carrier detection based on plasma Factor VIII levels. The cloning of genomic DNA and cDNA for human Factor VIII has been a starting point for at least a partial solution to each of these problems. Determination of the Factor VIII gene structure has elucidated the cause of hemophilia A in several patients. RFLPs within or near the Factor VIII gene have provided genetic markers that allow unambiguous assignment of carrier status and accurate prenatal diagnosis. This is generally accomplished by restriction enzyme digestion and Southern blotting of genomic DNA with Factor VIII probes. At present, a high degree of skill is required to perform and interpret these tests. The use of the so-called PCR method for the amplification of specific genomic DNA fragments promises to make these analyses faster and less technically demanding.

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Carrier detection in hemophilia A: a cooperative international study. II. The efficacy of a universal discriminant

Cited by 7 publications

References 0 publications

More Than Half the Sporadic Cases of Hemophilia A in Sweden Are Due to a Recent Mutation

More Than Half the Sporadic Cases of Hemophilia A in Sweden Are Due to a Recent Mutation

Genetic Counseling of Hemophilia Carriers

Recombinant DNA Methods in Hemophilia A: Carrier Detection and Prenatal Diagnosis*

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