Supplementary Table 1. Mutation detection rate in 21 studies on hemophilia B patients
Publication
Guo et al, 2014 [1]
Li et al, 2014 [2]
Rydz et al, 2013 [3]
Radic et al, 2013 [4]
Dai et al, 2012 [5]
Miller et al, 2012 [6]
Kwon et al, 2008 [7]
Jenkins et al, 2008 [8]
Belvini et al, 2005 [9]
Jayandharan et al, 2005 [10]
Mukherjee et al, 2004 [11]
Espinos et al, 2003 [12]
Onay et al, 2003 [13]
Ljung et al, 2001 [14]
Costa et al, 2000 [15]
Liu et al, 2000 [16]
Li et al, 2000 [17]
Wulff et al, 1999 [18]
Weinmann et al, 1998 [19]
Saad et al, 1994 [20]
Tartary et al, 1993 [21]
Total
No. index cases*
34
77
45
74
238
53
29
22
24
226
267
55
29
153
33
51
59
53
26
219
44
1811
No. mutations identified
34
77
45
69
236
53
24
22
24
225
249
55
27
152
33
50
58
47
26
217
40
1763
*Studies of at least 20 patients with hemophilia B were selected.
Detection
Rate
99.2
100
82.8
100
100
100
100
93.2
100
99.6
93.3
100
93.1
99.3
100
98
98.3
88.7
100
99.1
90.9
97.4
Goodeve AC. Hemophilia B: Molecular Pathogenesis and Mutation Analysis 1 of 6

Supplementary Table 2. Factor IX missense variant data from the Exome Aggregation Consortium
Variant (rs No.)
X:138612930 C / T
X:138612931 G / A (rs148060786)
X:138612942 A / T
X:138619330 A / G
X:138633223 C / T
Exon Protein Consequence
1 p.Arg3Cys
2
6
1
1 p.Arg3His p.Ile7Phe p.Thr84Ala p.Arg162Gln
Allele
Count*
15
32
110
12
10
Allele
Number† Allele Frequency F9db‡
122548 0.0001224 0
122572
122642
122308
118670
0.0002611
0.0008969
0.00009811
0.00008427
0
3
1
0
F9db
Severity§
-
-
Mi-Se
NK
-
X:138633280 A / G (rs6048)
X:138633358 T / A
X:138633379 G / A
X:138633412 T / G (rs143128467)
X:138642945 G / A
X:138643751 C / T (rs1801202)
X:138643811 G / A (rs150351950)
X:138643892 T / G (rs147567879)
6
6
6
6
7
8
8
8 p.Thr194Ala p.Ser220Thr p.Val227Ile p.Phe238Val p.Val247Ile p.His303Tyr p.Glu323Lys p.Ser350Ala
27346
34
10
13
20
62
107
13
122476
122892
122870
122528
122918
118648
121720
122744
0.2233
0.0002767
0.00008139
0.0001061
0.0001627
0.0005226
0.0008791
0.0001059
2
0
2
0
2
0
1
0
NK
-
Mo
-
Mi-Mo
-
Mi
-
X:138644190 G / A (rs143018900) 8 p.Arg449Gln 16 121490 0.0001317 14 Mi
X:138644225 A / C (rs4149751) 8 p.Thr461Pro 55 116378 0.0004726 0 -
Data obtained from ExAC (http://exac.broadinstitute.org/ & http://www.factorix.org accessed 15 November 2014), all ExAC missense variants are listed.
*Count of minor allele; † Total alleles analysed; ‡ No. reports on F9db; § Hemophilia B severity on F9db; Mild-Mi, Moderate-Mo, Severe
Goodeve AC. Hemophilia B: Molecular Pathogenesis and Mutation Analysis 2 of 6

Supplementary Table 3. Mutations associated with inhibitors in hemophilia B
Mutation type Mutation
Frameshift
Splice
Indel
Missense
Total
Large deletion Ex1-8
Ex1
Ex1-3
Ex1-5
Ex2-5
Nonsense
Ex2-7
Ex5-8
All large deletion p.Glu35* p.Ser49* p.Phe55* (c.164_173del) p.Phe55* (c.165_169del) p.Arg75* p.Gln237* (c.719G>A ) p.Gln237* (c.720G>A ) p.Trp240* p.Arg294* p.Arg298*
All nonsense p.Tyr22fs p.Ala26fs p.Thr85fs p.Phe87fs p.Glu323fs c.839-2A>C c.839-1G>A p.Ser411delinsGly p.Gln237Lys
Data from F9db ( http://www.factorix.org accessed 15 November 2014)
† Percentage too small to be relevant
1
1
1
1
1
23
1
1
1
1
1
62
4
4
1
1
1
8
1
1
Inhibitors
No.
21
1
1
30
1
1
1
3
2
Total patients No.
1
1
1
1
5
1
1
311
63
229
1
1
4
4
11
70
1
1
1
73
1
1
69
1
60
1
1
3
2
Mutation %
A further patient is reported in the literature to have a p.Gln241His missense mutation and an inhibitor, but is not reported on F9db under inhibitor entries [22].
-
-
-
-
6
2
10
-
-
20
-
-
20
11
25
25
36
-
-
-
-
-
-
-
43
35
-†
-
-
Goodeve AC. Hemophilia B: Molecular Pathogenesis and Mutation Analysis 3 of 6

Supplementary Table 4. Resources for Candidate Mutation Analysis
Resource
HGVS
Align GVGD
Mutation taster
PolyPhen-2
Purpose
Genetic nomenclature guideline
Amino acid conservation
Amino acid conservation
Amino acid conservation
SIFT
Gene Splicer
Amino acid conservation
Splice site prediction
Human Splicing Finder Splice site prediction
MaxEntScan Splice site prediction
Web address http://www.hgvs.org/mutnomen/ http://agvgd.iarc.fr/ http://www.mutationtaster.org/ http://genetics.bwh.harvard.edu/pph2/ http://sift.jcvi.org/ http://www.cbcb.umd.edu/software/GeneSplicer/gene_spl.shtml http://www.umd.be/HSF3/ http://genes.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html
NetGene2
NNSplice
Combined Annotation
Dependent Depletion
Splice site prediction
Splice site prediction
Deleteriousness scoring tool, examines various mutation types http://www.cbs.dtu.dk/services/NetGene2/ http://www.fruitfly.org/seq_tools/splice.html http://cadd.gs.washington.edu/
Several further links to pathogenicity analysis resources are available through the guideline documents from the ACGS [23] and ACMG [24].
Goodeve AC. Hemophilia B: Molecular Pathogenesis and Mutation Analysis 4 of 6

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