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

Ljung, Rolf; Kling, S.; Sjörin, Elsy; Nilsson, Inga Marie

doi:10.1111/j.1651-2227.1991.tb11860.x

Cited by 12 publications

(10 citation statements)

References 19 publications

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“…In this study, 24 mothers and 9 sisters of patients with HA in whom mutations were found were analyzed for carrier potential. The mothers of seven patients were carriers, and we confirmed that two-thirds of HA mutated alleles were transmitted from normal females [29].…”

Section: Discussionsupporting

confidence: 66%

Genotyping of Intron Inversions and Point Mutations in Exon 14 of the FVIII Gene in Iranian Azeri Turkish Families with Hemophilia A

Khaniani

Ebrahimi

Daraei

et al. 2016

Indian J Hematol Blood Transfus

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Hemophilia A (HA) is an inherited X-linked bleeding disorder caused by a variety of mutations that are distributed throughout the large FVIII gene (F8). The most common mutations in studied populations with severe HA are introns 22 and 1 inversions, gross exon deletions and point mutations in exon 14. The aim of this study was to define the frequency of these common mutations in Iranian population of Azeri Turkish in North West of Iran. Fifty patients with severe HA and forty-three female potential carriers were genotyped by inverse shifting polymerase chain reaction (IS-PCR), long-range PCR, multiplex PCR, and sequencing methods for the detection of Intron 22 and 1 inversions, gross exon deletions, and exon 14 point mutations, respectively. F8 intron 22 inversion was detected in 22 (44 %) out of 50 patients. Moreover, we detected one intron 1 inversion (2 %), and one point mutation in exon 14 (2 %). In this population, 52 % of the patients with hemophilia A did not show to carry a mutation in the analyzed regions by three mentioned methods. F8 intron 22 inversion was the major causative mutation in nearly 50 % of severe HA cases in an Azerbaijani Turkish population, which is similar to the incidence of other populations. IS-PCR is a robust, rapid, efficient, and costeffective method for the genetic analysis of patients with severe HA and for HA carrier detection, especially in developing countries.

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Section: Discussionsupporting

confidence: 66%

Genotyping of Intron Inversions and Point Mutations in Exon 14 of the FVIII Gene in Iranian Azeri Turkish Families with Hemophilia A

Khaniani

Ebrahimi

Daraei

et al. 2016

Indian J Hematol Blood Transfus

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“…In Sweden, haplotype analysis of a random sample of families with isolated, severe hemophilia A, suggested that at least 55% of mutations were sporadic occurrences within the past two generations [38]. In the current series, there was no family history of hemophilia in 70% of families whose affected members had severe and moderately severe hemophilia A.…”

Section: Discussionmentioning

confidence: 48%

Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions

1996

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Inversions between a gene A copy within intron 22 of the factor Vlll gene and additlonal copies outside the factor Vlll gene were found In 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy In 14, and a third (variant) copy in one. Baseline factor Vlll clotting activity levels were 1 1 % of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had 51% activity levels nor in 42 familles with moderately severe hemophllia A and 2-5% baseline levels. Both high titer and low level alloantibody lnhibltors were found in patients with or without an inversion. Of 13 high titer inhlbltors, 8 were perslstent and 1 of these patients had an inversion. Of 5 that responded to daily factor Vlll infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilla was Isolated in 30 and the mother was a carrier in the 25 In which addltlonal family members were informatlve. In three of these families with Isolated occurrence, the maternal grandmother was a carrier whereas in three others a de now mutatlon occurred in the maternal grandfather's factor Vlll gene. Screening for gene Inversions in patlents with severe (or "borderline" severe) hemo-philia A provides a direct marker of the mutation in 45% of families. It is useful even If there is no living affected member and In predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A.

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“…It has been shown that mothers of a sporadic case very often carry a de novo mutation and that the X-chromosome that carries the mutation often is derived from the sporadic boy's healthy maternal grandfather. 11,12 Thus, sisters to mothers of a sporadic case are often noncarriers. However, the extent of our knowledge today certainly does not allow us to exclude carriership in sporadic families.…”

Section: Genotype Assesment-direct Gene Analysismentioning

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

Cited by 12 publications

References 19 publications

Genotyping of Intron Inversions and Point Mutations in Exon 14 of the FVIII Gene in Iranian Azeri Turkish Families with Hemophilia A

Genotyping of Intron Inversions and Point Mutations in Exon 14 of the FVIII Gene in Iranian Azeri Turkish Families with Hemophilia A

Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions

Genetic Counseling of Hemophilia Carriers

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