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Hemophilia   B: molecular pathogenesis and mutation analysis

View Article: PubMed Central - PubMed

ABSTRACT

Hemophilia B is an X‐chromosome‐linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophilia B since the mid‐1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in > 97% of patients with hemophilia B. The risk of the development of inhibitory antibodies, which are reported in ~ 2% of patients with hemophilia B, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms, and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently ‘silent’ changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophilia B, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.

No MeSH data available.


Related in: MedlinePlus

Factor IX mutation type distribution in patients with hemophilia B on the F9 mutation database. Three thousand six hundred and fifty‐six mutations (P.M. Rallapalli, personal communication) are broken down by type in the larger pie chart. Point mutations are broken down by type in the smaller pie chart. ND, mutation type not determined.
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jth12958-fig-0001: Factor IX mutation type distribution in patients with hemophilia B on the F9 mutation database. Three thousand six hundred and fifty‐six mutations (P.M. Rallapalli, personal communication) are broken down by type in the larger pie chart. Point mutations are broken down by type in the smaller pie chart. ND, mutation type not determined.

Mentions: Several organizations recommend that mutation analysis should be performed for all patients with hemophilia, highlighting any excess risk of inhibitor development associated with specific mutations, and enabling carrier testing for female relatives and prenatal or possibly preimplantation genetic diagnosis. The first hemophilia B mutation was reported in 1985 19. Mutation analysis generally uses PCR DNA amplification followed by Sanger sequencing of the eight exons, the 5′‐untranslated region, the 3′‐untranslated region and splice boundaries of F9. In some laboratories, mutation scanning is used to highlight the amplicon containing a candidate mutation prior to its sequence analysis 20. Next‐generation DNA sequencing (NGS) is also being used to determine the F9 sequence 21. Variants comprise point mutations, deletions, insertions, duplications, insertions and deletions, complex changes, and neutral polymorphisms; the proportions currently in the F9db 7 are shown in Fig. 1. The largest proportion of patients with hemophilia B have missense mutations (65%).


Hemophilia   B: molecular pathogenesis and mutation analysis
Factor IX mutation type distribution in patients with hemophilia B on the F9 mutation database. Three thousand six hundred and fifty‐six mutations (P.M. Rallapalli, personal communication) are broken down by type in the larger pie chart. Point mutations are broken down by type in the smaller pie chart. ND, mutation type not determined.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496316&req=5

jth12958-fig-0001: Factor IX mutation type distribution in patients with hemophilia B on the F9 mutation database. Three thousand six hundred and fifty‐six mutations (P.M. Rallapalli, personal communication) are broken down by type in the larger pie chart. Point mutations are broken down by type in the smaller pie chart. ND, mutation type not determined.
Mentions: Several organizations recommend that mutation analysis should be performed for all patients with hemophilia, highlighting any excess risk of inhibitor development associated with specific mutations, and enabling carrier testing for female relatives and prenatal or possibly preimplantation genetic diagnosis. The first hemophilia B mutation was reported in 1985 19. Mutation analysis generally uses PCR DNA amplification followed by Sanger sequencing of the eight exons, the 5′‐untranslated region, the 3′‐untranslated region and splice boundaries of F9. In some laboratories, mutation scanning is used to highlight the amplicon containing a candidate mutation prior to its sequence analysis 20. Next‐generation DNA sequencing (NGS) is also being used to determine the F9 sequence 21. Variants comprise point mutations, deletions, insertions, duplications, insertions and deletions, complex changes, and neutral polymorphisms; the proportions currently in the F9db 7 are shown in Fig. 1. The largest proportion of patients with hemophilia B have missense mutations (65%).

View Article: PubMed Central - PubMed

ABSTRACT

Hemophilia B is an X‐chromosome‐linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophilia B since the mid‐1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in > 97% of patients with hemophilia B. The risk of the development of inhibitory antibodies, which are reported in ~ 2% of patients with hemophilia B, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms, and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently ‘silent’ changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophilia B, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.

No MeSH data available.


Related in: MedlinePlus