Supplementary Material
Supplemental Table S1: Variants associated with SIDS present in ESP
European
Americans
Ethnicity and
Amino
Gene
Variant
sex of SIDS
acid
Minor
Total
victims
allele
alleles
CAV3
c.40G>C
c.216C>G
p.V14L
p.C72W
c.233C>T
p.T78M
African
Americans
Minor
allele
All
Black male
-
0
15
8600
8600
14
3
Total Minor Total
alleles allele alleles Minor/
Minor
4406
14
13006
0
4406
18
13006
0
8600
18
4406
56
13006
0
Genotype
Minor/
Major/
Major
Major
14
6489
18
6485
56
6447
Family history / cosegregation
Functional data
Combined in
silico
prediction
-
Gain of function( INa)
-
Benign
Pathogenic
-
Gain of function (INa)
Benign
38
3
8600
0
4406
3
13006
0
3
6500
-
No effect
Pathogenic
(Van Norstrand et al., 2012)
14
0
8600
8600
0
11
4406
4406
14
11
13006
13006
0
0
14
11
6489
6492
Loss of function (INa)
-
Benign
Benign
(Van Norstrand et al., 2007)
(Tester and Ackerman, 2005)
-
Pathogenic
(Millat et al., 2009)
No effect
Loss of function
(KATP)
Gain of function (IKs)
Loss of function (IKs)
Gain of function (Ito)
Loss of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Gain of function (INa)
Pathogenic
Pathogenic
(Johnson et al., 2003)
(Arnestad et al., 2007)
Benign
(Tester and Ackerman, 2005)
Pathogenic
Benign
Benign
(Tester et al., 2011)
(Arnestad et al., 2007)
(Arnestad et al., 2007)
(Tester and Ackerman, 2005)
GJA1
c.814T>C
p.S272P*
GPD1L
KCNE2
c.370A>G
c.40G>A
p.I124V
p.V14I*
c.442G>A
p.R148W
White male
16
8600
0
4406
16
13006
0
16
6487
c.2653G>A
c.3470G>A
p.R885C
p.P1157L*
White infant
1
0
8600
8536
0
1
4406
4322
1
1
13006
12858
0
0
1
1
6502
6428
Familial mutation:
Father.Prolongated
QTc. Asymptomatic.
-
c.1036G>A
p.V346I
Black female
0
8600
4
4406
4
13006
0
4
6499
-
c.820A>G
KCNQ1 c.1378G>A
c.1799C>T
p.I274V
p.G460S
p.T600M*
White infant
White infant
Black female
1
1
0
8598
8598
8574
0
0
7
4402
4404
4380
1
1
7
13000
13002
12954
0
0
0
1
1
7
6499
6500
6470
SCN1B
c.774G>A
p.R214Q*
White female
21
4474
2
2482
23
6956
0
23
3455
SCN4B
c.617G>A
c.647G>A
c.2066G>A
c.2074G>T
c.3578G>A
c.3911G>A
c.5477G>A
c.5851C>A
c.6010A>G
c.6016G>C
c.784A>C
c.1378G>A
p.S206L
p.S216L
p.R689H
p.Q692K*
p.R1193Q
p.T1304M
p.R1826H
p.V1951L
p.F2004L
p.P2006A
p.T262P*
p.G460S
Black male
White infant
Black infant
White female
2 white infants
White infant
White male
White infant
3 white infants
2 white infants
White female
White female
2
11
1
2
11
4
1
5
26
13
2
0
8592
8432
8472
8480
8600
8468
8536
8394
8368
8364
8600
8600
0
1
0
0
0
1
1
19
2
1
0
1
4400
4090
4276
4276
4406
4176
4294
4158
4028
4012
4406
4406
2
12
1
2
11
5
2
24
28
14
2
1
12992
12522
12748
12756
13006
12644
12830
12552
12396
12376
13006
13006
0
0
0
0
0
0
0
0
1
0
0
0
2
12
1
2
11
5
2
24
26
14
2
1
6494
6249
6373
6376
6492
6317
6413
6252
6171
6174
6501
6502
-
KCNH2
SCN5A
SNTA1
(Cronk et al., 2007)
(Arnestad et al., 2007)
(Arnestad et al., 2007; Cronk et al.,
2007)
Black female
White female
+ white infant
White female
Black female
KCNJ8
References
*classified as unknown/suspected pathogenicity
Benign
Pathogenic
Pathogenic
Benign
Benign
Benign
Pathogenic
Benign
Benign
Benign
Benign
Benign
Pathogenic
(Hu et al., 2012)
(Tan et al., 2010)
(Arnestad et al., 2007)
(Plant et al., 2006)
(Millat et al., 2009)
(Arnestad et al., 2007)
(Arnestad et al., 2007)
(Ackerman et al., 2001)
(Arnestad et al., 2007)
(Arnestad et al., 2007)
(Arnestad et al., 2007)
(Cheng et al., 2009)
Supplemental Table S2: Variants associated with SIDS not present in ESP
Ethnicity and sex
Gene
Variant
Amino acid
Functional data
of SIDS victims
CAV3
c.236T>G
p.L79R
Black female
Gain of function( INa)
GJA1
c.124G>A
p.E42K
White male
Loss of intercellular coupling
c.247G>A
p.E83K
White male
Loss of function ( INa)
GPD1L
c.817C>T
p.R273C
White male
Loss of function ( INa)
KCNH2
KCNE1
KCNJ8
KCNQ1
RYR2
SCN3B
SCN5A
c.301A>G
p.K101E
-
-
c.818G>A
c.835G>A
c.881G>T
c.1764C>A
c.2684C>T
c.3118A>G
c.59C>T
c. del995_997GAA
c.314A>T
c.350C>T
c.1793A>G
p.R273Q
p.V279M
p.G294V
p.N588K
p.T895M*
p.S1040G
p.T20I
p.E332del
p.H105L
p.P117L
p.K598R*
White infant
White infant
White male
White infant
Japanese infant
White infant
White female
White male
Female
White infant
Japanese infant
Loss of function( IKr)
No effect
Gain of function( IKr)
Gain and loss of function( IKr)
Loss of function (KATP)
No effect
Loss of function ( IKs)
No effect
c.1876G>A
p.G626S
White male
-
c.13695C>A
c.36800G>A
p.S4565R
p.R2267H
White female
Black female
c.106G>A
p.V36M
White female
c.161A>C
c.1595T>G
p.V54G
p.F532C
White male
Japanese infant
Gain of function (ICa)
Gain of function (ICa)
Both Gain- and Loss of
function ( INa)
Loss of function ( INa)
No effect
c.1700T>A
p.L567Q
White female
Loss of function ( INa)
c.2039G>A
p.R680H
Gain of function ( INa)
c.2465G>A
p.W822X
White infant
2 white males
(twins)
Male
White male
White male
Japanese infant
Black infant
Male
White female
c.2971_2972delinsTC
p.S941N
c.2933C>T
p.R975W*†
c.2989G>T
p.A997S
c.3250C>A
p.G1084S*
c.3319A>G
p.E1107K
c.3988G>C
p.A1330P
c.3998C>A
p.S1333Y
Family history / co-segregation
References
De novo mutation. Family history of SIDS
Family history of unspecified cardiac arrhytmia.
Familial mutation: Maternal uncle with TdP and
prolonged QTc, Mother with marginally
increased QTc interval and history of syncope
Family history of SIDS and aborted SIDS
Familial mutation.
De novo mutation.
Familial mutation: Mother - asymptomatic
LQTS.
-
(Cronk et al., 2007)
(Van Norstrand et al., 2012)
(Van Norstrand et al., 2007)
(Van Norstrand et al., 2007)
(Christiansen et al., 2005)
(Arnestad et al., 2007)
(Arnestad et al., 2007; Rhodes et al., 2008)
(Tester and Ackerman, 2005)
(Brugada et al., 2004)
(Otagiri et al., 2008)
(Arnestad et al., 2007)
(Millat et al., 2009)
(Tester et al., 2011)
(Wedekind et al., 2006)
(Schwartz et al., 2001; Dahimène et al., 2006)
(Ackerman et al., 2003; Sharma et al., 2004)
(Otagiri et al., 2008)
(Millat et al., 2009)
(Tester et al., 2007)
-
(Tester et al., 2007)
Familial mutation: co-segregates with Brugada
syndrome of family members. Family history of
SCD's
-
(Tan et al., 2010)
(Otagiri et al., 2008)
(Arnestad et al., 2007)
Loss of function ( INa)
No family history.
(Turillazzi et al., 2008)
Gain of function ( INa)
No available data
Gain of function ( INa)
Loss of function ( INa)
Gain of function ( INa)
Gain of function ( INa)
De novo mutation. No family history.
De novo mutation.
De novo mutation
(Schwartz et al., 2000)
(Millat et al., 2009)
(Ackerman et al., 2001)
(Otagiri et al., 2008)
(Plant et al., 2006)
(Wedekind et al., 2001)
(Huang et al., 2009; Millat et al., 2009)
(Priori et al., 2000)
c.4456T>C
p.F1486L
White infant
Gain of function ( INa)
Familial mutation: Mother, brother, ant,
c.4867C>T
p.R1623X
Female
Loss of function ( INa)
grandfather. All with normal ECGs. Family
history of SIDS.
c.5114T>C
p.F1705S
Japanese girl
No effect
c.166G>A
p.P56S
3 black females
No effect
c.160C>G
p.G54R*
1 hispanic female
No effect
SNTA1
c.861C>G
p.S287R
White female
Gain of function (INa)
c.1115C>T
p.T372M
2 white males
Gain of function (INa)
*classified as unknown/suspected pathogenicity † have previously been found in other control populations
(Arnestad et al., 2007)
(Todd et al., 2005)
(Otagiri et al., 2008)
(Valdivia et al., 2002)
(Cheng et al., 2009)
(Cheng et al., 2009)
(Cheng et al., 2009)
Supplemental Table S3: Common polymorphisms associated with SIDS present in ESP
European
Americans
Gene
KCNE2
Variant
Amino
acid
African
Americans
All
Genotype
Minor
allele
Total
alleles
Minor Total Minor Total
allele alleles alelle alleles
Functional data
Minor/
Minor
Minor/
Major
Major/
Major
Combined in
silico
prediction
References
c.25G>C
p.Q9E
0
8600
73
4406
73
13006
0
73
6430
Loss of function
Benign
(Abbott et al., 1999; Arnestad et al.,
2007)
c.1571G>A
p.S524Y
7
8382
135
4080
142
12462
5
132
6094
Loss of function (INa)
Benign
(Plant et al., 2006; Shuraih et al., 2007)
c.3308C>A p.S1103Y
3
8448
304
4172
307
12620
9
289
6012
Gain of function (INa)
Benign
(Plant et al., 2006)
SCN5A
Supplemental Table S4: In silico predictions of the SIDS associated variants present in ESP.
Alignment across
Gene
Amino acid Grantham score
PolyPhen2
species
p.V14L
32
Not Conserved
Benign
CAV3
p.C72W
215
Conserved
Probably damaging
p.T78M
81
Not Conserved
Probably damaging
GJA1
p.S272P*
74
Conserved
Probably damaging
GPD1L
p.I124V
29
Conserved
Benign
KCNE2
p.V14I*
29
Not Conserved
Benign
p.R148W
101
Conserved
Benign
KCNH2
p.R885C
180
Conserved
Probably damaging
p.P1157L*
98
Conserved
Possibly damaging
KCNJ8
p.V346I
29
Conserved
Benign
p.I274V
29
Conserved
Probably damaging
KCNQ1
p.G460S
56
Not Conserved
Benign
p.T600M*
81
Conserved
Possibly damaging
SCN1B
p.R214Q*
43
Not Conserved
Benign
SCN4B
p.S206L
145
Conserved
Probably damaging
p.S216L
145
Conserved
Probably damaging
p.R689H
29
Not Conserved
Benign
p.Q692K*
53
Not Conserved
Benign
p.R1193Q
43
Not Conserved
Benign
SCN5A
p.T1304M
81
Conserved
Probably damaging
p.R1826H
29
Conserved
Possibly damaging
p.V1951L
32
Not Conserved
Benign
p.F2004L
22
Not Conserved
Benign
p.P2006A
27
Not Conserved
Benign
p.T262P*
38
Not Conserved
Benign
SNTA1
p.G460S
56
Conserved
Probably damaging
SIFT
Tolerated
Tolerated
Damaging
Damaging
Tolerated
Tolerated
Damaging
Damaging
Damaging
Tolerated
Damaging
Tolerated
Tolerated
Tolerated
Damaging
Damaging
Tolerated
Tolerated
Tolerated
Damaging
Tolerated
Tolerated
Tolerated
Tolerated
Damaging
Damaging
Combined in silico
prediction†
Benign
Pathogenic
Benign
Pathogenic
Benign
Benign
Pathogenic
Pathogenic
Pathogenic
Benign
Pathogenic
Benign
Benign
Benign
Pathogenic
Pathogenic
Benign
Benign
Benign
Pathogenic
Benign
Benign
Benign
Benign
Benign
Pathogenic
*classified as unknown/suspected pathogenicity †variants are classified as pathogenic if ≥3 of the in silico prediction toolspredicted pathogenicity or benign
if <3 predicted pathogenicity. Grantham values ≥100 were defined as radical changes (pathogenic), and values < 100 as conservative (benign). Polyphen-2
predictions “Probably damaging” and “possibly damaging” were considered “damaging” (pathogenic). The degree of conservation across species was
obtained from HGMD and all variants with ≥1 substitution were classified as not conserved/(benign).
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「綜説」遺伝性不整脈の機序と治療 渡部 裕 - 新潟県医師会

Rangliste 2016