The Clinical Genetics of Hemophilia B (Factor IX Deficiency)

Figures & data

Table 1 Frequency of Hemophilia A and Hemophilia B Patients by Severity Among Patients Attending US Hemophilia Treatment Centers²⁴

Type	n	Severity n (%)
		Severe	Moderate	Mild	Unknown
Hemophilia A	16,642	8011 (48.2)	3319 (19.9)	5024 (30.2)	288 (1.7)
Hemophilia B	5106	1467 (28.7)	2108 (41.3)	1423 (27.9)	108 (2.1)

Notes: Adapted with permission from Soucie JM, Miller CH, Dupervil B, Le B, Buckner TW. Occurrence rates of haemophilia among males in the United States based on surveillance conducted in specialized haemophilia treatment centres. Haemophilia. 2020;26(3):487–493. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.²⁴

Figure 1 Diagram of factor IX (FIX) gene and protein structure. (A) FIX gene (F9). (B). FIX protein showing amino acids numbered by Human Genome Variation Society nomenclature. (C). Activated FIX (FIXa). Domains include signal peptide (Signal), propeptide (Pro), gamma-carboxyglutamic acid (Gla), hydrophobic segment (H), epidermal growth factor (EGF) 1, EGF 2, linker peptide (L), activation peptide (Act), serine protease.

Table 2 Unique F9 Variants Reported to Cause Hemophilia B by Variant Type Classified by A. Type of Gene Change from Factor IX Gene (F9) Variant Database [http://www.factorix.org] and B. Type of Protein Change from CDC Hemophilia B Mutation Project [https://www.cdc.gov/ncbddd/hemophilia/champs.html

A. Type of Gene Change^Citation80	Number of Variants	% of Variants
Point mutation	800	76.7
Deletion	179	17.2
Insertion	37	3.5
Indel	17	1.6
Duplication	5	0.5
Complex	5	0.5
Total	1043	100.0
B. Type of Protein Change^Citation81	Number of Variants	% of Variants
Missense	657	58.1
Frameshift	182	16.1
Splice site change	106	9.4
Nonsense	91	8.0
Large structural change (>50 base pairs)	33	2.9
Promoter	25	2.2
Small structural change (in-frame, <50 base pairs)	23	2.0
3ʹ untranslated region	4	0.4
Synonymous	10	0.9
Total	1131	100.0

Notes: Adapted with permission from UCL. Factor IX Gene (F9) Variant Database. Available from: http://www.factorix.org/statistics.html.php.⁸⁰ Data from Centers for Disease Control and Prevention CHBMP F9 Mutation List.⁸¹

Figure 2 Distributions of factor IX activity in women heterozygous for variants causing hemophilia B (heterozygotes) and for women not having variants causing hemophilia (controls). Reproduced with permission from Miller CH, Bean CJ. Genetic causes of haemophilia in women and girls. Haemophilia. 2020;27(2):e164–e179. © Published 2020. This article is a U.S. Government work and is in the public domain in the USA.¹²

Soucie JM, Miller CH, Dupervil B, Le B, Buckner TW. Occurrence rates of haemophilia among males in the United States based on surveillance conducted in specialized haemophilia treatment centres. Haemophilia. 2020;26(3):487–493. doi:10.1111/hae.13998

 PubMed Web of Science ®Google Scholar

UCL. Factor IX Gene (F9) Variant Database. Available from: http://www.factorix.org/statistics.html.php. Accessed November 07, 2021.

 Google Scholar

Centers for Disease Control and Prevention. CHBMP F9 Database. Available from: https://www.cdc.gov/ncbddd/hemophilia/champs.html. Accessed October 19, 2021.

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Miller CH, Bean CJ. Genetic causes of haemophilia in women and girls. Haemophilia. 2021;27(2):e164–e179. doi:10.1111/hae.14186

 Web of Science ®Google Scholar