title: Mutation analysis of Swedish haemophilia B families - high frequency of unique mutations.
abstract: BACKGROUND
  Haemophilia B is caused by a heterogeneous spectrum of mutations. Mutation characterization is important in genetic counselling, prenatal diagnosis and to predict risk of inhibitor development.
  
  
  OBJECTIVE
  To study the mutation spectrum, frequency of unique recurrent mutations, genotype-phenotype association and inhibitor development in a population-based study of the complete Swedish haemophilia B population.
  
  
  METHODS
  The study included, facilitated by centralized DNA diagnostics, the complete registered Swedish haemophilia B population (113 families: 47 severe, 22 moderate and 44 mild), each represented by a single patient. Mutation characterization was performed by conventional sequencing of all exons and haplotyping by genotyping of single nucleotide variants and microsatellites.
  
  
  RESULTS
  A mutation was found in every family: eight had large deletions, three had small deletions (<10 base pair) and 102 had single base pair substitutions (69 missense, 26 nonsense, four splice site and three promoter). Ten novel mutations were found and were predicted to be deleterious. Sixteen mutations (one total gene deletion, 14 substitutions and one acceptor splice site) were present in more than one family. Of the single nucleotide mutations (37/102), 36% arose at CpG sites. Haplotyping of families with identical mutations and present analyses showed that the frequency of unique mutations was at least 65%. Inhibitors developed in 9/47 (19%) patients with severe haemophilia B.
  
  
  CONCLUSIONS
  The spectrum of haemophilia B mutations reveals at least 65% of the families carry a unique mutation, but with more inhibitor patients than reported internationally, probably as a result of many 'null' mutations.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Mårtensson
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Letelier
authors.affiliation: Biomedicine Kristianstad University, Kristianstad, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Halldén
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Ljung
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood; D018389:Codon, Nonsense; D004247:DNA / Q000302:isolation & purification / Q000378:metabolism; D004252:DNA Mutational Analysis; D005164:Factor IX / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D002836:Hemophilia B / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D022821:RNA Splice Sites; D017384:Sequence Deletion; D012720:Severity of Illness Index; D013548:Sweden
chemical_list: D057134:Antibodies, Neutralizing; D018389:Codon, Nonsense; D022821:RNA Splice Sites; D005164:Factor IX; D004247:DNA
keywords: F9 gene; factor IX; haemophilia B; haplotype analysis; inhibitor; mutation