Hemophilia B: Molecular pathogenesis and mutation analysis

Journal of Thrombosis and Haemostasis

Volumn 13, Issue 7, 2015, Pages 1184-1195

  Goodeve, A C ^a  

^a UNIVERSITY OF SHEFFIELD   (United Kingdom)

Author keywords

DNA mutational analysis; Factor IX; Genetic carrier detection; Hemophilia B; Prenatal diagnosis

Indexed keywords

ANTIBODY; BLOOD CLOTTING FACTOR 9; BLOOD CLOTTING FACTOR 9 ANTIBODY; MESSENGER RNA; UNCLASSIFIED DRUG;

DISEASE SEVERITY; DRUG DOSE ESCALATION; F9 GENE; GENE DELETION; GENE DOSAGE; GENE DUPLICATION; GENE INSERTION; GENE THERAPY; HEMOPHILIA B; HETEROZYGOTE; HUMAN; MOLECULAR PATHOLOGY; MOSAICISM; MUTATIONAL ANALYSIS; NONHUMAN; NONSENSE MUTATION; PATHOGENICITY; PHASE 1 CLINICAL TRIAL (TOPIC); PHENOTYPE; POLYMERASE CHAIN REACTION; PRENATAL DIAGNOSIS; PRIORITY JOURNAL; PROGNOSIS; QUALITY CONTROL; REVIEW; RIBOSOME; RNA ANALYSIS; RNA SPLICING; SEQUENCE ANALYSIS; SEX RATIO; SINGLE NUCLEOTIDE POLYMORPHISM; ANIMAL; BLOOD; DNA MUTATIONAL ANALYSIS; FEMALE; GENETIC PREDISPOSITION; GENETICS; HEMOSTASIS; MALE; METABOLISM; MUTATION; PREDICTIVE VALUE; RISK FACTOR; SEVERITY OF ILLNESS INDEX; SEX DIFFERENCE;

ANIMALS; DNA MUTATIONAL ANALYSIS; FACTOR IX; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HEMOPHILIA B; HEMOSTASIS; HETEROZYGOTE; HUMANS; MALE; MUTATION; PHENOTYPE; PREDICTIVE VALUE OF TESTS; PRENATAL DIAGNOSIS; PROGNOSIS; RISK FACTORS; SEVERITY OF ILLNESS INDEX; SEX FACTORS;

EID: 84935698157     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.12958     Document Type: Review

References (100)

1. Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR, Merskey C. Christmas disease - a condition previously mistaken for haemophilia. Br Med J 1952; 2: 1378-82.
2. Puetz J, Soucie JM, Kempton CL, Monahan PE, Hemophilia Treatment Center Network Investigators. Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database. Haemophilia 2014; 20: 25-31.
3. UKHCDO. UK National Haemophilia Database Bleeding Disorder Statistics for 2013-2014http://www.ukhcdo.org/annReport.htm. Accessed 2 February 2015.
4. Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985; 24: 3736-50.
5. Stonebraker JS, Bolton-Maggs PH, Michael Soucie J, Walker I, Brooker M. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 2012; 18: e91-4.
6. Rallapalli PM. Factor IX Variant Databasehttp://www.factorix.org/. Accessed 15 November 2014.
7. Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013; 11: 1329-40.
8. HGNC. HUGO Gene Nomenclature Committee information homepagehttp://www.genenames.org/. Accessed 15 November 2014.
9. HGVS. Nomenclature for the description of sequence variations homepagehttp://www.hgvs.org/mutnomen/. Accessed 20 December 2014.
10. Ensembl. Ensembl Genome browser homepagehttp://www.ensembl.org/index.html. Accessed 31 January 2015.
11. Giannelli F, Green PM, High KA, Lozier JN, Lillicrap DP, Ludwig M, Olek K, Reitsma PH, Goossens M, Yoshioka A, Sommer S, Brownlee GG. Haemophilia B: database of point mutations and short additions and deletions. Nucleic Acids Res 1990; 18: 4053-9.
12. Green P. Haemophilia B Mutation Databasehttp://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html. Accessed 3 December 2010.
13. Mannucci PM, Franchini M. Is haemophilia B less severe than haemophilia A? Haemophilia 2013; 19: 499-502.
14. Clausen N, Petrini P, Claeyssens-Donadel S, Gouw SC, Liesner R, PedNet, Research of Determinants of Inhibitor Development Study Group. Similar bleeding phenotype in young children with haemophilia A or B: a cohort study. Haemophilia 2014; 20: 747-55.
15. Tagariello G, Iorio A, Santagostino E, Morfini M, Bisson R, Innocenti M, Mancuso ME, Mazzucconi MG, Pasta GL, Radossi P, Rodorigo G, Santoro C, Sartori R, Scaraggi A, Solimeno LP, Mannucci PM, Italian Association Hemophilia Centre. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009; 114: 779-84.
16. Schulman S, Eelde A, Holmstrom M, Stahlberg G, Odeberg J, Blomback M. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost 2008; 6: 1113-21.
17. Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, van Amstel HK, van der Bom JG, van Diemen-Homan JE, Willemse J, Rosendaal FR. Bleeding in carriers of hemophilia. Blood 2006; 108: 52-6.
18. Sharathkumar A, Hardesty B, Greist A, Salter J, Kerlin B, Heiman M, Sulkin M, Shapiro A. Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C->T mutation. Haemophilia 2009; 15: 91-100.
19. Rees DJ, Rizza CR, Brownlee GG. Haemophilia B caused by a point mutation in a donor splice junction of the human factor IX gene. Nature 1985; 316: 643-5.
20. Mitchell M, Keeney S, Goodeve A. Practice Guidelines for the Molecular Diagnosis of Haemophilia Bhttp://www.acgs.uk.com/media/774631/haemophilia_b_bpg_revision_sept_2011_approved.pdf. Accessed 15 January 2015.
21. Josephson NC, Martin B, Nakaya S, Konkle BA, Luk A, Pierce GF, Shendure J, O'Roak B. A next generation sequencing approach for genotyping patients with hemophilia. J Thromb Haemost 2013; 11: 85-289.
22. Chan V, Au P, Lau P, Chan TK. A novel haemophilia B defect due to partial duplication of the factor IX gene. Br J Haematol 1994; 86: 601-9.
23. Kwon MJ, Yoo KY, Kim HJ, Kim SH. Identification of mutations in the F9 gene including exon deletion by multiplex ligation-dependent probe amplification in 33 unrelated Korean patients with haemophilia B. Haemophilia 2008; 14: 1069-75.
24. Casana P, Haya S, Cid AR, Oltra S, Martinez F, Cabrera N, Aznar JA. Identification of deletion carriers in hemophilia B: quantitative real-time polymerase chain reaction or multiple ligation probe amplification. Transl Res 2009; 153: 114-17.
25. Payne AB, Bean CJ, Hooper WC, Miller CH. Utility of multiplex ligation-dependent probe amplification (MLPA) for hemophilia mutation screening. J Thromb Haemost 2012; 10: 1951-4.
26. Solera J, Magallon M, Martin-Villar J, Coloma A. Factor IXMadrid 2: a deletion/insertion in factor IX gene which abolishes the sequence of the donor junction at the exon IV-intron d splice site. Am J Hum Genet 1992; 50: 434-7.
27. Vidaud D, Vidaud M, Bahnak BR, Siguret V, Gispert Sanchez S, Laurian Y, Meyer D, Goossens M, Lavergne JM. Haemophilia B due to a de novo insertion of a human-specific Alu subfamily member within the coding region of the factor IX gene. Eur J Hum Genet 1993; 1: 30-6.
28. Wulff K, Gazda H, Schroder W, Robicka-Milewska R, Herrmann FH. Identification of a novel large F9 gene mutation - an insertion of an Alu repeated DNA element in exon e of the factor 9 gene. Hum Mutat 2000; 15: 299.
29. Mukherjee S, Mukhopadhyay A, Banerjee D, Chandak GR, Ray K. Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients. Haemophilia 2004; 10: 259-63.
30. Feng J, Liu Q, Drost J, Sommer SS. Deep intronic mutations are rarely a cause of hemophilia B. Hum Mutat 1999; 14: 267-8.
31. Chavali S, Ghosh S, Bharadwaj D. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics 2009; 94: 433-7.
32. Sarkar G, Yoon HS, Sommer SS. Screening for mutations by RNA single-strand conformation polymorphism (rSSCP): comparison with DNA-SSCP. Nucleic Acids Res 1992; 20: 871-8.
33. van de Water NS, Tan T, May S, Browett PJ, Harper P. Factor IX polypyrimidine tract mutation analysis using mRNA from peripheral blood leukocytes. J Thromb Haemost 2004; 2: 2073-5.
34. Green PM, Rowley G, Giannelli F. Unusual expression of the F9 gene in peripheral lymphocytes hinders investigation of F9 mRNA in hemophilia B patients. J Thromb Haemost 2003; 1: 2675-6.
35. Cutler JA, Mitchell MJ, Savidge GF. More on: unusual expression of the F9 gene in peripheral lymphocytes hinders investigation of F9 mRNA in hemophilia B patients. J Thromb Haemost 2004; 2: 1021.
36. Cao DH, Liu XL, Mu K, Ma XW, Sun JL, Bai XZ, Lin CK, Jin CL. Identification and genetic analysis of a factor IX gene intron 3 mutation in a hemophilia B pedigree in China. Turk J Haematol 2014; 31: 226-30.
37. Pezeshkpoor B, Zimmer N, Marquardt N, Nanda I, Haaf T, Budde U, Oldenburg J, El-Maarri O. Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. J Thromb Haemost 2013; 11: 1679-87.
38. Castaman G, Giacomelli SH, Mancuso ME, D'Andrea G, Santacroce R, Sanna S, Santagostino E, Mannucci PM, Goodeve A, Rodeghiero F. Deep intronic variations may cause mild hemophilia A. J Thromb Haemost 2011; 9: 1541-8.
39. Pezeshkpoor B, Pavlova A, Oldenburg J, El-Maarri O. F8 genetic analysis strategies when standard approaches fail. Hamostaseologie 2014; 34: 167-73.
40. Kasper CK, Lin JC. Prevalence of sporadic and familial haemophilia. Haemophilia 2007; 13: 90-2.
41. Jenkins PV, Egan H, Keenan C, O'Shea E, Smith OP, Nolan B, White B, O'Donnell J. Mutation analysis of haemophilia B in the Irish population: increased prevalence caused by founder effect. Haemophilia 2008; 14: 717-22.
42. Kasper CK, Buzin CH. Mosaics and haemophilia. Haemophilia 2009; 15: 1181-6.
43. Karimipoor M, Zeinali S, Nafissi N, Tuddenham EG, Lak M, Safaee R. Identification of factor IX mutations in Iranian haemophilia B patients by SSCP and sequencing. Thromb Res 2007; 120: 135-9.
44. Orstavik KH, Scheibel E, Ingerslev J, Schwartz M. Absence of correlation between X chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of haemophilia A and B. Thromb Haemost 2000; 83: 433-7.
45. Di Michele DM, Gibb C, Lefkowitz JM, Ni Q, Gerber LM, Ganguly A. Severe and moderate haemophilia A and B in US females. Haemophilia 2014; 20: e136-43.
46. Knoll A, Ketterling RP, Sommer SS. Absence of somatic mosaicism in 17 families with hemophilia B: an analysis with a sensitivity 10- to 1000-fold greater than that of sequencing gels. Hum Genet 1996; 98: 539-45.
47. Sommer SS, Knoll A, Greenberg CR, Ketterling RP. Germline mosaicism in a female who seemed to be a carrier by sequence analysis. Hum Mol Genet 1995; 4: 2181-2.
48. Green PM, Saad S, Lewis CM, Giannelli F. Mutation rates in humans. I. Overall and sex-specific rates obtained from a population study of hemophilia B. Am J Hum Genet 1999; 65: 1572-9.
49. Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet 2013; 14: 307-20.
50. Peake IR, Lillicrap DP, Boulyjenkov V, Briet E, Chan V, Ginter EK, Kraus EM, Ljung R, Mannucci PM, Nicolaides K, Tuddenham EGD. Report of a joint WHO/WFH meeting on the control of haemophilia: carrier detection and prenatal diagnosis. Blood Coagul Fibrinolysis 1993; 4: 313-44.
51. Jayandharan GR, Srivastava A, Srivastava A. Role of molecular genetics in hemophilia: from diagnosis to therapy. Semin Thromb Hemost 2012; 38: 64-78.
52. Dai J, Lu Y, Ding Q, Wang H, Xi X, Wang X. The status of carrier and prenatal diagnosis of haemophilia in China. Haemophilia 2012; 18: 235-40.
53. Bors A, Andrikovics H, Illes Z, Jager R, Kardos M, Marosi A, Nemes L, Tordai A. Carrier and prenatal diagnostic strategy and newly identified mutations in Hungarian haemophilia A and B families. Blood Coagul Fibrinolysis 2015; 26: 161-6.
54. Cutler J, Chappell LC, Kyle P, Madan B. Third trimester amniocentesis for diagnosis of inherited bleeding disorders prior to delivery. Haemophilia 2013; 19: 904-7.
55. Peyvandi F, Garagiola I, Mortarino M. Prenatal diagnosis and preimplantation genetic diagnosis: novel technologies and state of the art of PGD in different regions of the world. Haemophilia 2011; 17(Suppl. 1): 14-17.
56. Belvini D, Salviato R, Acquila M, Bicocchi MP, Frusconi S, Garagiola I, Sanna V, Santacroce R, Rocino A, Tagariello G. Prenatal diagnosis of haemophilia B: the Italian experience. Haemophilia 2013; 19: 898-903.
57. Exome Aggregation Consortium. ExAC Browser. http://exac.broadinstitute.org/. Accessed 30 November 2014.
58. National Centre for Biotechnology Information. NCBI dbSNPhttp://www.ncbi.nlm.nih.gov/sites/entrez. Accessed 29 January 2015.
59. NHLBI. Exome Sequencing Project (ESP)http://evs.gs.washington.edu/EVS/. Accessed 29 January 2015.
60. Montandon AJ, Green PM, Bentley DR, Ljung R, Kling S, Nilsson IM, Giannelli F. Direct estimate of the haemophilia B (factor IX deficiency) mutation rate and of the ratio of the sex-specific mutation rates in Sweden. Hum Genet 1992; 89: 319-22.
61. Green PM, Bentley DR, Mibashan RS, Nilsson IM, Giannelli F. Molecular pathology of haemophilia B. EMBO J 1989; 8: 1067-72.
62. Knobe KE, Sjorin E, Ljung RC. Why does the mutation G17736A/Val107Val (silent) in the F9 gene cause mild haemophilia B in five Swedish families? Haemophilia 2008; 14: 723-8.
63. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 2011; 12: 683-91.
64. Pinotti M, Caruso P, Canella A, Campioni M, Tagariello G, Castaman G, Giacomelli S, Belvini D, Bernardi F. Ribosome readthrough accounts for secreted full-length factor IX in hemophilia B patients with nonsense mutations. Hum Mutat 2012; 33: 1373-6.
65. Veltkamp JJ, Meilof J, Remmelts HG, van der Vlerk D, Loeliger EA. Another genetic variant of haemophilia B: haemophilia B Leyden. Scand J Haematol 1970; 7: 82-90.
66. Crossley M, Winship PR, Austen DE, Rizza CR, Brownlee GG. A less severe form of haemophilia B Leyden. Nucleic Acids Res 1990; 18: 4633.
67. Funnell AP, Wilson MD, Ballester B, Mak KS, Burdach J, Magan N, Pearson RC, Lemaigre FP, Stowell KM, Odom DT, Flicek P, Crossley M. A CpG mutational hotspot in a ONECUT binding site accounts for the prevalent variant of hemophilia B Leyden. Am J Hum Genet 2013; 92: 460-7.
68. Funnell AP, Crossley M. Hemophilia B Leyden and once mysterious cis-regulatory mutations. Trends Genet 2014; 30: 18-23.
69. Kurachi S, Huo JS, Ameri A, Zhang K, Yoshizawa AC, Kurachi K. An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden. Proc Natl Acad Sci USA 2009; 106: 7921-6.
70. Hildyard C, Keeling D. Effect of age on factor IX levels in symptomatic carriers of haemophila B Leyden. Br J Haematol 2015; 169: 448-9.
71. Mukherjee S, Mukhopadhyay A, Chaudhuri K, Ray K. Analysis of haemophilia B database and strategies for identification of common point mutations in the factor IX gene. Haemophilia 2003; 9: 187-92.
72. Bottema CD, Ketterling RP, Vielhaber E, Yoon HS, Gostout B, Jacobson DP, Shapiro A, Sommer SS. The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene. Hum Genet 1993; 91: 496-503.
73. Hallden C, Martensson A, Nilsson D, Sall T, Lind-Hallden C, Liden AC, Ljung R. Origin of Swedish hemophilia B mutations. J Thromb Haemost 2013; 11: 2001-8.
74. Feng J, Drost JB, Scaringe WA, Liu Q, Sommer SS. Mutations in the factor IX gene (F9) during the past 150 years have relative rates similar to ancient mutations. Hum Mutat 2002; 19: 49-57.
75. Sommer SS, Scaringe WA, Hill KA. Human germline mutation in the factor IX gene. Mutat Res 2001; 487: 1-17.
76. Liu JZ, Li X, Drost J, Thorland EC, Liu Q, Lind T, Roberts S, Wang HY, Sommer SS. The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation. Hum Mutat 2000; 16: 31-6.
77. Li X, Drost JB, Roberts S, Kasper C, Sommer SS. Factor IX mutations in South Africans and African Americans are compatible with primarily endogenous influences upon recent germline mutations. Hum Mutat 2000; 16: 371.
78. Ghosh K, Shetty S, Quadros L, Kulkarni B. Double mutations causing haemophilia B: a double whammy! Br J Haematol 2009; 145: 433-5.
79. Chen SH, Zhang M, Lovrien EW, Scott CR, Thompson AR. CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series. Hum Genet 1991; 87: 177-82.
80. Saini S, Hamasaki-Katagiri N, Pandey GS, Yanover C, Guelcher C, Simhadri VL, Dandekar S, Guerrera MF, Kimchi-Sarfaty C, Sauna ZE. Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B. Haemophilia 2015; 21: 210-18.
81. Warrier I, Lusher JM. Development of anaphylactic shock in haemophilia B patients with inhibitors. Blood Coagul Fibrinolysis 1998; 9(Suppl. 1): S125-8.
82. Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency: a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia 2009; 15: 1027-31.
83. Wallis Y, Payne S, McAnulty C, Bodmer D, Sistermans E, Robertson K, Moore D, Abbs S, Deans Z, Devereau A. Practice Guidelines for the Evaluation of Pathogenicity and the Reporting of Sequence Variants in Clinical Molecular Geneticshttp://www.acgs.uk.com/media/774853/evaluation_and_reporting_of_sequence:variants_bpgs_june_2013_-_finalpdf.pdf. Accessed 20 December 2014
84. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-23.
85. Hamasaki-Katagiri N, Salari R, Simhadri VL, Tseng SC, Needlman E, Edwards NC, Sauna ZE, Grigoryan V, Komar AA, Przytycka TM, Kimchi-Sarfaty C. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia 2012; 18: 933-40.
86. Mukherjee S, Saha A, Biswas P, Mandal C, Ray K. Structural analysis of factor IX protein variants to predict functional aberration causing haemophilia B. Haemophilia 2008; 14: 1076-81.
87. Bicocchi MP, Pasino M, Rosano C, Molinari AC, Della Valle E, Lanza T, Bottini F, Acquila M. Insight into molecular changes of the FIX protein in a series of Italian patients with haemophilia B. Haemophilia 2006; 12: 263-70.
88. UK NEQAS. United Kingdom National External Quality Assessment Service for Molecular Genetics homepagewww.ukneqasbc.org/. Accessed 31 January 2015.
89. Perry DJ, Cumming T, Goodeve A, Hill M, Jennings I, Kitchen S, Walker I. The UK National External Quality Assessment Scheme for heritable bleeding disorders. Semin Thromb Hemost 2014; 40: 261-8.
90. Perry DJ, Goodeve A, Hill M, Jennings I, Kitchen S, Walker I, UK NEQAS for Blood Coagulation. The UK National External Quality Assessment Scheme (UK NEQAS) for molecular genetic testing in haemophilia. Thromb Haemost 2006; 96: 597-601.
91. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014; 371: 1994-2004.
92. Thompson AR, Bajaj SP, Chen SH, MacGillivray RT. 'Founder' effect in different families with haemophilia B mutation. Lancet 1990; 335: 418.
93. Li T, Miller CH, Driggers J, Payne AB, Ellingsen D, Hooper WC. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol 2014; 89: 375-9.
94. Mahajan A, Chavali S, Kabra M, Chowdhury MR, Bharadwaj D. Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene. Haematologica 2004; 89: 1498-503.
95. Saad S, Rowley G, Tagliavacca L, Green PM, Giannelli F. First report on UK database of haemophilia B mutations and pedigrees. UK Haemophilia Centres. Thromb Haemost 1994; 71: 563-70.
96. Wulff K, Schroder W, Wehnert M, Herrmann FH. Twenty-five novel mutations of the factor IX gene in haemophilia B. Hum Mutat 1995; 6: 346-8.
97. McGraw RA, Davis LM, Lundblad RL, Stafford DW, Roberts HR. Structure and function of factor IX: defects in haemophilia B. Clin Haematol 1985; 14: 359-83.
98. Thompson AR, Schoof JM, Weinmann AF, Chen SH. Factor IX mutations: rapid, direct screening methods for 20 new families with hemophilia B. Thromb Res 1992; 65: 289-95.
99. Koeberl DD, Bottema CD, Buerstedde JM, Sommer SS. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG. Am J Hum Genet 1989; 45: 448-57.
100. Bottema CD, Ketterling RP, Yoon HS, Sommer SS. The pattern of factor IX germ-line mutation in Asians is similar to that of Caucasians. Am J Hum Genet 1990; 47: 835-41.