Supplemental Table 1. KCNQ1 variants by location, type of variant, functional effect and parental transmission
Location
Variant type
Function
Total
families
Total Mater Pater
Patient
carriers transm transm LOVD ID
Amino acid change
Nucleotide change
p.(Pro74Serfs*210)
p.(Val100Cysfs*137)
c.220_221delCC
c.298delG
N-terminus
N-terminus
frameshift
frameshift
haploinsufficiency
haploinsufficiency
1
1
3
3
0
1
2
1
p.(Tyr111Cys)
c.332A>G
N-terminus
missense
dominant negative (1)
3
9
6
0
p.(Asn112dup)
c.334_336dup
N-terminus
in-frame
insertion
unknown
1
2
0
1
49186
p.(Pro117Leu)
c.350C>T
N-terminus
missense
1
3
0
2
49187
p.(Gly119Arg)
p.(His126Asp)
p.0? ?
p.(Tyr148*)
p.0?
c.355G>C
c.376C>G
c.386+5G>A
c.444T>A
c.477+1G>A
N-terminus
S1-S4
S1-S4
S1-S4
S1-S4
missense
missense
splice site
nonsense
splice site
non-dominant negative
(1)
unknown
unknown
haploinsufficiency
haploinsufficiency
haploinsufficiency
1
1
1
1
1
3
2
3
5
3
2
1
2
4
1
0
0
0
0
1
p.0?
c.477+5G>A
S1-S4
splice site
haploinsufficiency
2
6
3
1
p.0?
c.478-2A>T
S1-S4
splice site
haploinsufficiency
1
6
0
4
p.(Gly168Arg)
c.502G>A
S1-S4
missense
dominant negative (2)(3)
3
11
7
0
p.(Glu170Gly)
p.(Tyr171Asn)
c.509A>G
c.511T>A
S1-S4
S1-S4, C-loop
missense
missense
unknown
unknown
1
1
2
2
1
1
0
0
p.(Arg174Cys)
c.520C>T
S1-S4, C-loop
missense
dominant negative (4)
6
33
14
11
p.(Arg174His)
c.521G>A
S1-S4, C-loop
missense
unknown
5
19
9
4
49188
49189
49190
49191
49192
49193
49194
49195
49196
49197
49198
49199
49200
49201
49202
49203
49204
49205
49206
49207
49208
49209
49210
49181
49182
49183
49184
49185
49211
49212
49213
49214
49215
49216
49217
49218
49219
p.(Gly179Serfs*62)
c.524_534dupTCTGGTCCGCC
S1-S4, C-loop
frameshift
haploinsufficiency
2
8
2
3
p.(Ala178Thr)
p.(Gly179Ser)
p.(Lys183Arg)
c.532G>A
c.535G>A
c.548A>G
S1-S4, C-loop
S1-S4, C-loop
S1-S4, C-loop
missense
missense
missense
unknown
unknown
unknown
1
1
1
7
2
2
0
1
0
5
0
1
p.(Tyr184Ser)
c.551A>C
S1-S4, C-loop
missense
dominant negative (2)
3
24
11
9
p.(Gly186_Leu187del)
c.556_561delGGCCTC
S1-S4, C-loop
unknown
1
5
2
1
49220
p.(Gly186Asp)
c.557G>A
S1-S4, C-loop
in-frame
deletion
missense
unknown
1
2
1
0
p.(Gly189Glu)
c.566G>A
S1-S4, C-loop
missense
unknown
3
16
11
1
p.(Arg190Trp)
c.568C>T
S1-S4, C-loop
missense
unknown
3
8
2
2
p.(Arg190Leu)
c.569G>T
S1-S4, C-loop
missense
unknown
1
6
2
2
p.(Arg190Gln)
c.569G>A
S1-S4, C-loop
missense
dominant negative
(3)(5)(6)
7
39
16
13
p.(Val205Met)
c.613G>A
S1-S4
unknown
1
2
1
0
p.(Val207_Val212del)
c.619_636delGTGGCCTCCATGGTGGTC
S1-S4
unknown
1
3
2
0
49237
p.(Gln220Argfs*17)
c.657delG
S1-S4
missense
in-frame
deletion
frameshift
49221
49222
49223
49224
49225
49226
49227
49228
49229
49230
49231
49232
49233
49234
49235
49236
haploinsufficiency
1
3
0
2
p.(Ser225Leu)
c.674C>T
S1-S4
missense
dominant negative
(2)(3)(7)
9
70
40
16
49238
49239
49240
49241
49242
49243
49244
49245
49246
49247
49248
49249
49250
49251
49252
49253
49254
49255
49256
49257
49258
49259
49260
49261
49262
49263
49264
49265
49266
49267
49268
49269
p.(Ala226Val)
c.677C>T
S1-S4
missense
unknown
1
3
2
0
p.0?
c.683+5G>A
S1-S4
splice site
haploinsufficiency
2
4
1
1
p.0?
c.684-1G>C
S1-S4
splice site
haploinsufficiency
1
2
0
1
p.(Arg231Cys)
c.691C>T
S1-S4
missense
non-dominant negative
(8)(9)
5
15
9
2
p.(Arg231His)
p.(Val241Ile)
c.692G>A
c.721G>A
S1-S4
S1-S4
missense
missense
unknown
unknown
1
1
2
2
0
1
1
0
p.(Asp242Asn)
c.724G>A
S1-S4, C-loop
missense
unknown
2
5
2
1
p.(Arg243Cys)
c.727C>T
S1-S4, C-loop
missense
dominant negative (2)(3)
4
29
15
8
p.(Arg243His)
c.728G>A
S1-S4, C-loop
missense
non-dominant negative
(4)(9)
5
33
9
13
p.(Trp248Phe)
c.743_744delinsTC
S1-S4, C-loop
missense
non-dominant negative
(10)
1
3
0
2
49270
16
49271
49272
49273
49274
49275
49276
49277
49278
49279
49280
49281
49282
p.(Val254Met)
c.760G>A
S1-S4, C-loop
missense
dominant negative
(2)(3)(5)(11)
12
48
19
p.(Val254Leu)
c.760G>T
S1-S4, C-loop
missense
unknown
1
4
0
2
p.(His258Pro)
c.773A>C
S1-S4, C-loop
missense
unknown
3
8
3
2
p.(His258Arg)
p.(Arg259Cys)
p.(Arg259Leu)
p.?
S1-S4, C-loop
S1-S4, C-loop
S1-S4, C-loop
S1-S4, C-loop
missense
missense
missense
splice site
unknown
dominant negative (12)
unknown
unknown
1
1
1
1
2
2
2
2
0
1
1
1
1
0
0
0
p.?
c.773A>G
c.775C>T
c.776G>T
c.780+1G>T
c.780+2_780+20del
49283
49284
49285
49286
49287
49288
49289
49290
S1-S4, C-loop
splice site
unknown
1
3
0
2
49291
p.(Glu261Lys)
p.(Glu261Leu)
p.(Glu261Gly)
c.781G>A
c.781_782delinsTT
c.782A>G
S1-S4, C-loop
S1-S4, C-loop
S1-S4, C-loop
missense
missense
missense
unknown
unknown
unknown
1
1
1
2
2
9
0
1
4
1
0
4
p.(Gly269Ser)
c.805G>A
S5-pore-S6
missense
unknown (2)(4)(13)
11
31
10
9
p.(Gly269Asp)
p.(Gly272Asp)
p.(Ile274Val)
c.806G>A
c.815G>A
c.820A>G
S5-pore-S6
S5-pore-S6
S5-pore-S6
dominant negative (4)
unknown
unknown
1
1
1
3
2
4
2
1
2
0
0
1
p.(Ser277del)
c.828_830delCTC
S5-pore-S6
missense
missense
missense
in-frame
deletion
49292
49294
49293
49295
49296
49297
49298
49299
49300
49301
49302
49303
49304
49305
49306
49307
49308
haploinsufficiency (14)
1
2
1
0
49309
p.(Ser277Trp)
c.830C>G
S5-pore-S6
missense
unknown
2
4
1
2
p.(Ser277Leu)
c.830C>T
S5-pore-S6
missense
dominant negative (15)(16)
2
10
3
4
p.(Val280Ala)
p.(Ala283Asp)
p.(Glu284Lys)
p.(Val288Trpfs*60)
c.839T>C
c.848C>A
c.850G>A
c.862_880del
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
missense
missense
frameshift
unknown
unknown
unknown
haploinsufficiency
1
1
1
1
2
2
3
8
1
1
2
2
0
0
0
4
49310
49311
49312
49313
49314
49315
49316
49317
p.(Phe296Ser)
p.(Ala300Thr)
p.(Ala302Glu)
p.(Leu303Arg)
p.(Leu303Pro)
p.(Trp305Ser)
c.887T>C
c.898G>A
c.905C>A
c.908T>G
c.908T>C
c.914G>C
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
missense
missense
missense
missense
missense
unknown
non-dominant negative (7)
unknown
unknown
unknown
unknown (2)(4)
1
1
1
1
1
1
5
3
3
2
8
6
3
2
0
1
4
2
1
0
2
0
1
2
p.(Gly306Arg)
c.916G>A
S5-pore-S6
missense
dominant negative (5)
2
4
1
1
p.(Val307Trpfs*47)
p.?
p.(Thr309Arg)
p.(Thr311Ala)
p.(Thr311Ile)
p.(Thr312Ile)
p.(Ile313Lys)
c.919delG
c.922-2A>G
c.926C>G
c.931A>G
c.932C>T
c.935C>T
c.938_939delinsAA
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
frameshift
splice site
missense
missense
missense
missense
missense
haploinsufficiency
unknown
unknown
unknown
unknown
dominant negative (3)(17)
unknown
1
1
1
1
1
1
1
3
2
2
3
2
6
2
2
1
0
0
1
2
1
0
0
1
2
1
2
0
p.(Gly314Ser)
c.940G>A
S5-pore-S6
missense
dominant negative
(2)(4)(18)(19)
9
29
15
4
p.(Tyr315Cys)
c.944A>G
S5-pore-S6
missense
dominant negative (2)(20)
1
3
2
0
p.(Tyr315Ser)
c.944A>C
S5-pore-S6
missense
dominant negative (4)
4
30
16
8
p.(Gly316Glu)
c.947G>A
S5-pore-S6
missense
unknown
3
11
5
2
p.(Asp317Asn)
c.949G>A
S5-pore-S6
missense
unknown
1
2
1
0
p.(Pro320Ala)
c.958C>G
S5-pore-S6
missense
dominant negative (21)
3
21
3
11
49318
49319
49320
49321
49322
49323
49324
49325
49326
49327
49328
49329
49330
49331
49332
49333
49334
49335
49336
49337
49338
49339
49340
49341
49342
49343
49344
49345
49346
49347
49348
49349
49350
49351
49352
49353
p.(Pro320Ser)
p.(Pro320His)
c.958C>T
c.959C>A
S5-pore-S6
S5-pore-S6
missense
missense
unknown
dominant negative (21)
1
1
2
3
1
2
0
0
p.(Thr322Met)
c.965C>T
S5-pore-S6
missense
unknown
5
13
3
3
p.(Gly325Arg)
c.973G>A
S5-pore-S6
missense
dominant negative (15)(22)
10
26
13
3
p.(Gly325Glu)
p.(Ser338Cys)
p.(Phe339Ser)
c.974G>A
c.1013C>G
c.1016T>C
S5-pore-S6
S5-pore-S6
S5-pore-S6
unknown
unknown
unknown
1
1
1
2
2
4
1
1
3
0
0
0
p.(Phe340del)
c. 1017_1019delTTC
S5-pore-S6
missense
missense
missense
in-frame
deletion
unknown
2
5
2
1
p.(Ala341Val)
c.1022C>T
S5-pore-S6
missense
dominant negative (19)
10
42
20
10
p.(Leu342Phe)
c.1024C>T
S5-pore-S6
Missense
dominant negative *
1
5
5
0
p.(Ala344Val)
c.1031C>T
S5-pore-S6
Missense
unknown
3
23
14
2
p.Ala344sp
c.1031C>A
S5-pore-S6
splice site
dominant negative *
6
16
4
6
49354
49355
49356
49357
49358
49359
49360
49361
49362
49363
49364
49365
49366
49367
49368
49369
49370
49371
49372
49373
49374
49375
49376
49377
49378
49379
49380
49381
49382
49383
49384
49385
49386
49387
49388
49389
49390
p.Ala344sp
c.1032G>A
S5-pore-S6
splice site
dominant negative (23)
12
41
23
5
p.?
p.?
p.?
p.?
p.(Gly350Arg)
p.(Gly350Val)
c.1032+1G>A
c.1032+3A>G
c.1032+5G>A
c.1032+5G>C
c.1048G>C
c.1049G>T
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
splice site
splice site
splice site
splice site
missense
missense
unknown
Unknown (24)
unknown
unknown
unknown
unknown
1
1
1
1
1
1
3
2
8
5
5
3
2
1
1
4
2
2
0
0
6
0
0
0
p.(Gln356*)
c.1066C>T
C-terminus
Nonsense
haploinsufficiency
2
5
2
1
p.(Gln359_Lys362del)
c.1077_1088del GAGGCAGAAGCA
C-terminus
in-frame
deletion
unknown
3
11
4
2
p.(Lys362Arg)
p.(Asn365Lys)
c.1085A>G
c.1095C>G
C-terminus
C-terminus
Missense
Missense
unknown
unknown
1
1
7
2
4
1
0
0
p.(Arg366Trp)
c.1096C>T
C-terminus
Missense
unknown
5
21
11
3
p.(Arg366Pro)
p.(Arg366Gln)
c.1097G>C
c.1097G>A
C-terminus
C-terminus
Missense
Missense
unknown
unknown
1
3
2
13
1
9
0
0
49391
49392
49393
49394
49395
49396
49397
49398
49399
49400
49401
49402
49403
49404
49405
49406
49407
49408
49409
49410
49411
49412
49413
49414
49415
49416
49417
49418
49419
49420
49421
49422
49423
49424
49425
49426
49427
p.(Ala371Thr)
p.(Ser373Pro)
c.1111G>A
c.1117T>C
C-terminus
C-terminus
Missense
Missense
unknown
unknown
1
1
2
12
1
2
0
9
p.(Ile375Argfs*43)
c.1124_1127delTTCA
C-terminus
frameshift
haploinsufficiency
2
6
4
0
p.(Trp379Ser)
p.(Arg380Ser)
p.(Arg397Trp)
c.1136G>C
c.1140G>T
c.1189C>T
C-terminus
C-terminus
C-terminus
Missense
Missense
Missense
unknown
unknown
unknown
1
1
1
4
2
5
3
1
0
0
0
4
p.(Phe423Valfs*40)
c.1265dupA
C-terminus
frameshift
Haploinsufficiency
2
8
3
3
p.(Lys422Thr)
p.(Glu449Argfs*14)
p.(Pro448Glnfs*18)
c.1265A>C
c.1343dupC
c.1343delC
C-terminus
C-terminus
C-terminus
Unknown
Haploinsufficiency
Haploinsufficiency
1
1
1
2
9
2
1
6
1
0
1
0
p.(Gln505delinsCysAl
a)
c.1513_1514del insTGTGC
C-terminus
Unknown
1
8
4
2
49442
p.(Ile517Thr)
p.(Arg518Gly)
p.(Arg518*)
c.1550T>C
c.1552C>G
c.1552C>T
C-terminus
C-terminus
C-terminus
missense
frameshift
frameshift
in-frame
deletion
insertion
missense
missense
nonsense
49428
49429
49430
49431
49432
49433
49434
49435
49436
49437
49438
49439
49440
49441
Unknown
Unknown
Haploinsufficiency
1
1
1
3
2
2
2
1
1
0
0
0
p.(Met520Arg)
c.1559T>G
C-terminus
missense
Unknown
2
8
5
0
p.(Ala525Val)
c.1574C>T
C-terminus
missense
Unknown
2
4
2
0
p.(Gln530*)
p.(Ala532Glu)
c.1588C>T
c.1595C>A
C-terminus
C-terminus
nonsense
missense
Haploinsufficiency
Unknown
1
1
2
4
1
3
0
0
p.(Arg539Trp)
c.1615C>T
C-terminus
missense
non-dominant negative (6)
3
13
6
4
p.(Gln544Valfs*49)
c.1630_1637delinsGTTGAGA
C-terminus
frameshift
Haploinsufficiency
3
8
0
4
p.(Tyr545Cys)
c.1634A>G
C-terminus
missense
Unknown
1
3
2
0
p.(Arg555Cys)
c.1663C>T
C-terminus
missense
dominant negative (3)(4)
5
62
41
15
49443
49444
49445
49446
49447
49448
49449
49450
49451
49452
49453
49454
49455
49456
49457
49458
49459
49460
49461
p.(Arg555His)
p.(Arg561Ser)
p.(Asp564His)
p.(Ser566Pro)
c.1664G>A
c.1683G>T
c.1690G>C
c.1696T>C
C-terminus
C-terminus
C-terminus
C-terminus
missense
missense
missense
missense
Unknown
Unknown
Unknown
Unknown
1
1
1
1
8
4
4
3
3
3
3
2
2
0
0
0
p.(Ile567Thr)
c.1700T>C
C-terminus
missense
Unknown
2
11
6
3
p.(Pro570Leu)
c.1709C>T
C-terminus
missense
Unknown
2
7
4
1
p.(Leu572Cysfs*21)
p.0?
p.(Arg583Cys)
p.(Thr587Arg)
c.1714delC
c.1732+2T>C
c.1747C>T
c.1760C>G
C-terminus
C-terminus
C-terminus
C-terminus
frameshift
splice site
missense
missense
Haploinsufficiency
Haploinsufficiency
Unknown
Unknown (25)(26)
1
1
1
1
3
2
3
3
2
0
2
2
0
1
0
0
p.(Thr587Met
c.1760C>T
C-terminus
missense
Unknown (25)(26)
11
30
14
4
p.(Ala590Thr)
c.1768G>A
C-terminus
missense
Unknown
1
5
4
0
p.(Arg591His)
c.1772G>A
C-terminus
missense
non-dominant negative (2)
13
43
17
9
49462
49463
49464
49465
49466
49467
49468
49469
49470
49471
49472
49473
49474
49475
49476
49477
49478
49479
49480
49481
49482
49483
49484
49485
49486
49487
49488
49489
49490
49491
49492
49493
49494
49495
49496
49497
49498
3
11
6
2
1
1
1
1
2
2
2
2
1
1
1
1
0
0
0
0
1
4
1
2
49508
frameshift
Haploinsufficiency
Unknown
Haploinsufficiency
Haploinsufficiency
non-dominant negative
(2)(28)
Haploinsufficiency
49499
49500
49501
49502
49503
49504
49505
49506
49507
1
4
1
1
C-terminus
frameshift
Haploinsufficiency
2
5
2
1
C-terminus
frameshift
Haploinsufficiency
1
2
0
1
49509
49510
49511
49512
p.(Arg594Gln)
c.1781G>A
C-terminus
missense
p.(Arg594*)
p.(Lys598Arg)
p.(Asp603Thrfs*63)
p.(Gln604*)
c.1780C>T
c.1793A>G
c.1807delG
c.1810C>T
C-terminus
C-terminus
C-terminus
C-terminus
nonsense
missense
frameshift
nonsense
p.(Asp611Tyr)
c.1831G>T
C-terminus
missense
p.(Pro631Hisfs*14)
c.1892_1911del
C-terminus
p.(Arg632Glufs*34)
c.1893delC
p.(His637Thrfs*29)
c.1909delC
non-dominant negative
(2)(27)
Supplemental Table 1. KCNQ1 variants by location, type of variant, functional effect and parental transmission: Genetic alterations of the amino acid
sequence were characterized by location, and by type of variant (missense, splice site, in-frame deletions, nonsense, and frameshift). The nucleotide and amino
acid designations were based on the KCNQ1 reference sequences NM_000218.2 and NG_008935.1. Exons are numbered like in Splawski et al 1998 (29). The
variants were categorized by their location in the encoded channel as follows: variants in the transmembrane region, either in S1-S4 or in S5-pore-S6 defined as
amino acid residues from 124-262 and 263 to 355; in the C-loop region, defined as the sequence involving amino acid residues from 171 to 195 and from 242
to 262; in the remaining N-terminus region, defined as amino acid residues before 120, and the C-terminus region, defined as after residue 355.
We classified the variants into four groups: (1) missense variants with proven dominant negative, or (2) non-dominant negative effects based on published coexpression studies of variant and wild type channels, (3) variants leading to haploinsufficiency, and (4) with unknown consequences.
The group with haploinsufficiency contains the nonsense and frameshift variants and some splice variants as defined below.
Splice variants were classified either according to published studies or to expected consequences of exon(s) splicing. KCNQ1 exons 6 to 9 have numbers
of nucleotides which are multiple of 3 and their splicing does not induce frameshift. Thus, splice variants in introns 1, 2, 3, 4 and 14 were classified as
expecting to lead to frameshift and haploinsufficiency, while the variant affecting the acceptor site at the 3' end of the intron 7 (c.922-2 A>G) was classified as
unknown. The c.1032G>A (p.A344sp) variant, which changes the last base of the exon 7 induces splicing of exons 7 and 8 and in-frame transcripts and these
shorter channels were associated with a clear dominant negative effect on wild channels (23). The other splice variants of the donor site at the 5’ end of the
intron 7 (c.1032 +1 G>A, +3 A>G, +5 G>A, + 5 G>C) induce probably also in-frame transcripts but in much lower amounts as recently shown by TsujiWakisaka and coworkers (24). These variants were thus classified in group of variants with unknown consequences. Nucleotide changes in exon 7 close to the
exon-intron junction might cause exon skipping. As shown below, we amplified mRNA from patient lymphoblastoid cell lines with KCNQ1 primers,
p.Ala344Val had the same pattern as control subjects and was thus considered to belong to the missense variant group with unknown consequences, while
p.Ala344Glu and p.Leu342Phe showed patterns similar toA344spl with shorter transcripts likely causing the same dominant negative effect (*) as p.A344spl.
Two missense variants identified in patients with recessive Romano-Ward without congenital deafness (p.Gly269Ser, p.Trp305Ser), leading to an intermediate
dysfunction as illustrated by discrepancies between the published studies, could not be easily classified and were thus included in the group with unknown
effect.
References
1.
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2.
Jons C, O-Uchi J, Moss AJ, Reumann M, Rice JJ, Goldenberg I, Zareba W, Wilde AAM, Shimizu W, Kanters JK, McNitt S, Hofman N, Robinson JL,
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3.
Barsheshet A, Goldenberg I, O-Uchi J, Moss AJ, Jons C, Shimizu W, Wilde AA, McNitt S, Peterson DR, Zareba W, Robinson JL, Ackerman MJ,
Cypress M, Gray DA, Hofman N, Kanters JK, Kaufman ES, Platonov PG, Qi M, Towbin JA, Vincent GM, Lopes CM. Mutations in cytoplasmic loops of the
KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome.
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4.
Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell
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5.
Wang Z, Tristani-Firouzi M, Xu Q, Lin M, Keating MT, Sanguinetti MC. Functional effects of mutations in KvLQT1 that cause long QT syndrome. J.
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6.
Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J. Novel mutations in KvLQT1 that affect Iks
activation through interactions with Isk. Cardiovasc. Res. 2000 Mar;45(4):971–980.
7.
Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M, Schwartz PJ, Brown AM. Mechanisms of I(Ks) suppression in LQT1
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8.
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9.
Itoh H, Sakaguchi T, Ding W-G, Watanabe E, Watanabe I, Nishio Y, Makiyama T, Ohno S, Akao M, Higashi Y, Zenda N, Kubota T, Mori C, Okajima
K, Haruna T, Miyamoto A, Kawamura M, Ishida K, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Sugimoto Y, Ashihara T, Hayashi H, Ito M, Imoto K,
Matsuura H, Horie M. Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. Circ Arrhythm Electrophysiol. 2009
Oct;2(5):511–523.
10.
Ohno S, Kubota T, Yoshida H, Tsuji K, Makiyama T, Yamada S, Kuga K, Yamaguchi I, Kita T, Horie M. A novel mutation associated with Jervell and
Lange-Nielsen syndrome in a Japanese family. Circ. J. 2008 May;72(5):687–693.
11.
Wedekind H, Schwarz M, Hauenschild S, Djonlagic H, Haverkamp W, Breithardt G, Wülfing T, Pongs O, Isbrandt D, Schulze-Bahr E. Effective longterm control of cardiac events with beta-blockers in a family with a common LQT1 mutation. Clin. Genet. 2004 Mar;65(3):233–241.
12.
Kubota T, Shimizu W, Kamakura S, Horie M. Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of
KCNQ1. J. Cardiovasc. Electrophysiol. 2000 Sep;11(9):1048–1054.
13.
Murray A, Potet F, Bellocq C, Baró I, Reardon W, Hughes HE, Jeffery S. Mutation in KCNQ1 that has both recessive and dominant characteristics. J.
Med. Genet. 2002 Sep;39(9):681–685.
14.
Gouas L, Bellocq C, Berthet M, Potet F, Demolombe S, Forhan A, Lescasse R, Simon F, Balkau B, Denjoy I, Hainque B, Baró I, Guicheney P. New
KCNQ1 mutations leading to haploinsufficiency in a general population; Defective trafficking of a KvLQT1 mutant. Cardiovasc. Res. 2004 Jul 1;63(1):60–68.
15.
Aidery P, Kisselbach J, Schweizer PA, Becker R, Katus HA, Thomas D. Impaired ion channel function related to a common KCNQ1 mutation implications for risk stratification in long QT syndrome 1. Gene. 2012 Dec 10;511(1):26–33.
16.
Chen J, Weber M, Um SY, Walsh CA, Tang Y, McDonald TV. A dual mechanism for I(Ks) current reduction by the pathogenic mutation KCNQ1S277L. Pacing Clin Electrophysiol. 2011 Dec;34(12):1652–1664.
17.
Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T, Blanar MA. Dominant-negative KvLQT1 mutations underlie the LQT1
form of long QT syndrome. Circulation. 1997 Sep 16;96(6):1733–1736.
18.
Li W, Du R, Wang Q-F, Tian L, Yang J-G, Song Z-F. The G314S KCNQ1 mutation exerts a dominant-negative effect on expression of KCNQ1
channels in oocytes. Biochem. Biophys. Res. Commun. 2009 May 29;383(2):206–209.
19.
Brink PA, Crotti L, Corfield V, Goosen A, Durrheim G, Hedley P, Heradien M, Geldenhuys G, Vanoli E, Bacchini S, Spazzolini C, Lundquist AL,
Roden DM, George AL Jr, Schwartz PJ. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.
Circulation. 2005 Oct 25;112(17):2602–2610.
20.
Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A, Acquaro G, Priori SG. Evidence for a cardiac ion channel mutation
underlying drug-induced QT prolongation and life-threatening arrhythmias. J. Cardiovasc. Electrophysiol. 2000 Jun;11(6):691–696.
21.
Thomas D, Khalil M, Alter M, Schweizer PA, Karle CA, Wimmer A-B, Licka M, Katus HA, Koenen M, Ulmer HE, Zehelein J. Biophysical
characterization of KCNQ1 P320 mutations linked to long QT syndrome 1. J. Mol. Cell. Cardiol. 2010 Jan;48(1):230–237.
22.
Burgess DE, Bartos DC, Reloj AR, Campbell KS, Johnson JN, Tester DJ, Ackerman MJ, Fressart V, Denjoy I, Guicheney P, Moss AJ, Ohno S, Horie
M, Delisle BP. High-Risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K(+) Permeation. Biochemistry.
2012 Nov 2;
23.
Tsuji K, Akao M, Ishii TM, Ohno S, Makiyama T, Takenaka K, Doi T, Haruna Y, Yoshida H, Nakashima T, Kita T, Horie M. Mechanistic basis for the
pathogenesis of long QT syndrome associated with a common splicing mutation in KCNQ1 gene. J. Mol. Cell. Cardiol. 2007 Mar;42(3):662–669.
24.
Tsuji-Wakisaka K, Akao M, Ishii TM, Ashihara T, Makiyama T, Ohno S, Toyoda F, Dochi K, Matsuura H, Horie M. Identification and functional
characterization of KCNQ1 mutations around the exon 7-intron 7 junction affecting the splicing process. Biochim. Biophys. Acta. 2011 Nov;1812(11):1452–
1459.
25.
Biliczki P, Girmatsion Z, Brandes RP, Harenkamp S, Pitard B, Charpentier F, Hébert TE, Hohnloser SH, Baró I, Nattel S, Ehrlich JR. Traffickingdeficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization: evidence for
clinically significant IKr-IKs alpha-subunit interaction. Heart Rhythm. 2009 Dec;6(12):1792–1801.
26.
Hayashi K, Shuai W, Sakamoto Y, Higashida H, Yamagishi M, Kupershmidt S. Trafficking-competent KCNQ1 variably influences the function of
HERG long QT alleles. Heart Rhythm. 2010 Jul;7(7):973–980.
27.
Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen
syndrome. Cardiovasc. Res. 2001 Sep;51(4):670–680.
28.
Yamaguchi M, Shimizu M, Ino H, Terai H, Hayashi K, Kaneda T, Mabuchi H, Sumita R, Oshima T, Hoshi N, Higashida H. Compound heterozygosity
for mutations Asp611-->Tyr in KCNQ1 and Asp609-->Gly in KCNH2 associated with severe long QT syndrome. Clin. Sci. 2005 Feb;108(2):143–150.
29.
Splawski I, Shen J, Timothy KW, Vincent M, Lehman MH, Keating MT. Genomic structure of three long QT syndrome genes. Genomics. 1998 Jul;
51(1):86-97.
c.1032G>A
(p.A344spl)
c.1031C>T
(p.A344V)
Control
1000 bp
606 bp
510 bp (skipping of exon 8)
399 bp (skipping of exons 7 and 8)
500 bp
---
--Exon 7
Intron 7
- - - TTGCGCTCCCAGCG /gtaggtgcccc - - 1024
1031 1032
-
Supplemental Table 2. KCNH2 and SCN5A variants by location, type of variant and parental transmission
p.0?
p.(Thr13Asn)
Nucleotide
change
c.2T>G
c.38C>A
3
4
Maternal
transmission
2
3
Paternal
transmission
0
0
Patient
LOVD ID
49515
49516
N-terminus
N-terminus
KCNH2
p.(Asp16_Ile19del)
c.45_56delGG
N-terminus
1
9
5
1
49517
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Ile19Thr)
p.(Arg20Leu)
p.(Leu28Serfs*32)
p.(Ile42Ser)
p.(Tyr43Asp)
p.(Cys44Gly)
p.(Cys44Phe)
p.(Asn45Lys)
p.(Cys49Arg)
p.(Glu50Serfs*10)
c.56T>C
c.59G>T
c.81delT
c.125T>G
c.127T>G
c.130T>G
c.131G>T
c.135C>A
c.145T>C
c.148delG
1
1
1
1
1
1
1
1
1
1
4
3
3
2
3
3
6
2
8
2
0
2
0
0
2
2
2
1
6
1
2
0
2
1
0
0
3
0
1
0
missense
2
5
0
3
N-terminus
missense
2
7
2
2
c.167G>A
N-terminus
missense
1
3
2
0
p.(Glu58Lys)
c.172G>A
N-terminus
missense
2
6
1
3
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Cys64Tyr)
p.(Phe68Val)
p.(Gly71Arg)
p.(Pro72Leu)
p.(Pro72Gln)
p.(Gln75*)
c.191G>A
c.202T>G
c.211G>A
c.215C>T
c.215C>A
c.223C>T
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
missense
missense
missense
missense
missense
nonsense
1
1
1
1
1
1
6
2
2
14
2
5
3
1
0
5
1
4
0
0
1
8
0
0
KCNH2
p.(Leu87Pro)
c.260T>C
N-terminus
missense
2
8
2
3
49518
49519
49520
49521
49522
49524
49523
49525
49526
49527
49530
49531
49528
49529
49532
49533
49534
49535
49536
49537
49538
49539
49540
49541
49542
KCNH2
p.(Gly53Ser)
KCNH2
Gene
Amino acid change
KCNH2
KCNH2
Location
Variant type
Total families
Total carriers
1
1
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
nonsense
missense
in-frame
deletion
missense
missense
frameshift
missense
missense
missense
missense
missense
missense
frameshift
c.157G>A
N-terminus
p.(Gly53Asp)
c.158G>A
KCNH2
p.(Arg56Gln)
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Lys93Arg)
p.(Tyr99Ser)
p.(Arg100Gly)
p.(Phe106Val)
p.(Asp111Val)
c.278A>G
c.296A>C
c.298C>G
c.316T>G
c.332A>T
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
missense
missense
missense
missense
missense
1
1
1
1
1
2
13
4
2
3
1
2
1
1
1
0
8
0
0
0
KCNH2
p.(Pro114Ser)
c.340C>T
N-terminus
missense
2
6
2
2
KCNH2
KCNH2
KCNH2
p.(Val115Met)
p.(Met124Thr)
p.(Thr152Profs*14)
c.343G>A
c.371T>C
c.453delC
N-terminus
N-terminus
N-terminus
missense
missense
frameshift
1
1
1
2
4
2
1
0
1
0
2
0
KCNH2
p.(Thr152Hisfs*180)
c.453dupC
N-terminus
frameshift
2
5
1
1
KCNH2
p.(Pro157Alafs*176)
N-terminus
frameshift
1
2
1
0
49556
KCNH2
p.(Arg159Glnfs*174)
N-terminus
frameshift
1
4
0
3
49543
KCNH2
KCNH2
KCNH2
KCNH2
p.(Lys161Glnfs*171)
p.(Phe163Profs*168)
p.(Arg176Alafs*14)
p.(Glu177Ter)
p.(Gly187_Gly189del
)
p.(Pro191_Ala193del
)
p.(Asp197Tyr)
p.(Pro241Leu)
p.(Arg242Alafs*118)
p.(Ala244Serfs*112)
N-terminus
N-terminus
N-terminus
N-terminus
frameshift
frameshift
frameshift
nonsense
in-frame
deletion
1
1
1
1
4
3
3
2
3
0
2
1
0
2
0
0
49557
49558
49559
49560
1
3
2
0
49561
N-terminus
deletion
1
3
0
2
49562
N-terminus
N-terminus
N-terminus
N-terminus
missense
missense
frameshift
frameshift
in-frame
deletion
frameshift
frameshift
frameshift
Missense
missense
1
1
1
1
4
8
4
2
0
3
3
1
3
1
0
0
49563
49564
49565
49566
1
7
1
3
49567
1
1
1
1
1
2
5
5
3
2
1
4
2
0
1
0
0
0
2
0
49568
49569
49571
49570
49572
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
c.468_469insGC
CC
c.475_476insAG
GC
c.480dupC
c.486_487delCT
c.525_558del
c.529G>T
c.560_568delGC
GCGGGCG
c.567_575del
c.589G>T
c.722C>T
c.724delC
c.730_742del
c.754_756delCG
p.(Arg252del)
G
p.(His254Thrfs*101)
c.760_775del
p.(Arg273Glufs*87)
c.817delC
p.(Pro297Thrfs*35) c.888delGinsAA
p.(Pro297Ser)
c.889C>T
p.(Met308Val)
c.922A>G
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
N-terminus
49544
49545
49546
49547
49548
49549
49550
49551
49552
49554
49553
49555
KCNH2
KCNH2
KCNH2
p.(Arg312Hisfs*13)
p.(Pro334Leu)
p.(Gln335*)
KCNH2
p.(Thr337Tyrfs*19)
KCNH2
p.(Lys364Metfs*3)
KCNH2
KCNH2
p.(Arg366*)
p.0?
KCNH2
p.?
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Gln391*)
p.(Trp398*)
p.(His402Arg)
p.(Pro426His)
p.(Tyr427Cys)
p.(Asn428Leu)
c.933-952del
c.1001C>T
c.1003C>T
c.1008_1009ins
T
c.1091_1102deli
ns(53)
c.1096C>T
c.1129-1G>A
c.1128+1892_16
78dup
c.1171C>T
c.1193G>A
c.1205A>G
c.1277C>A
c.1280A>G
c.1283C>T
KCNH2
p.Val454Trpfs*67
c.1360delA
N-terminus
N-terminus
N-terminus
frameshift
missense
nonsense
1
1
1
2
3
3
1
2
0
0
0
2
N-terminus
frameshift
2
13
6
5
N-terminus
frameshift
2
7
1
4
N-terminus
N-terminus
nonsense
splice site
1
1
2
25
0
18
1
2
49573
49574
49575
49576
49577
49578
49579
49580
49581
N-terminus
frameshift
1
13
3
7
49582
N-terminus
S1-S4
S1-S4
S1-S4
S1-S4
S1-S4
nonsense
nonsense
missense
missense
missense
missense
1
1
1
1
1
1
2
3
2
3
2
2
1
0
0
0
0
1
0
2
1
2
1
0
49583
49584
49585
49586
49587
49588
S1-S4
frameshift
1
3
0
2
49592
in-frame
insertion
1
13
6
5
49589
missense
2
8
2
2
frameshift
1
2
1
0
49590
49591
49593
frameshift
1
2
0
1
49594
missense
1
3
2
0
49595
49596
49597
49598
49599
49600
49601
49602
c.1384_1401du
p
S1-S4
ATGTTCATTGTG
GACATC
KCNH2
p.(Met462Leu467dup)
KCNH2
p.(Phe463Leu)
KCNH2
p.(Leu468Profs*51)
KCNH2
p.(His485Glnfs*40)
KCNH2
p.(Pro486Arg)
KCNH2
p.(His492Tyr)
c.1474C>T
S1-S4
missense
2
4
1
1
KCNH2
p.(Trp497*)
c.1491G>A
S1-S4
nonsense
1
3
2
0
KCNH2
p.(Asp501Asn)
c.1501G>A
S1-S4
missense
2
8
6
0
KCNH2
KCNH2
p.0?
p.(Arg534Cys)
c.1557+1G>A
c.1600C>T
S1-S4
S1-S4
splice site
missense
1
3
3
17
1
4
0
9
c.1389C>G
S1-S4
c.1402dup
S1-S4
c.1436_1454du
S1-S4
p
c.1457C>G
S1-S4
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Leu553Val)
p.(Phe557Leufs*8)
p.(Ala558Pro)
p.(Ala561Thr)
p.(Ala561Val)
c.1657C>G
c.1671delT
c.1672G>C
c.1681G>A
c.1682C>T
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
frameshift
missense
missense
missense
1
1
1
1
1
5
7
4
5
2
1
4
0
3
1
3
1
3
0
0
KCNH2
p.(His562Arg)
c.1685A>G
S5-pore-S6
missense
3
18
3
9
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.( Trp563Gly)
p.(Trp563*)
p.( Trp563Cys)
p.(Ala565Ser)
p.(Cys566Ser)
p.(Trp568*)
p.(Tyr569Cys)
p.(Gly572Cys)
c.1687T>G
c.1689G>A
c.1689G>T
c.1693G>T
c.1696T>A
c.1704G>A
c.1706A>G
c.1714G>T
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
nonsense
missense
missense
missense
nonsense
missense
missense
1
1
1
1
1
1
1
1
2
3
2
2
9
3
4
4
1
0
1
1
1
0
3
3
0
2
0
0
5
2
0
0
KCNH2
p.(Gly572Ser)
c.1714G>A
S5-pore-S6
missense
4
10
4
2
KCNH2
KCNH2
KCNH2
p.(Gly572Asp)
p.(Met574Val)
p.(Glu575*)
c.1715G>A
c.1720A>G
c.1723G>T
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
missense
nonsense
in-frame
deletion
1
1
1
2
3
3
1
2
0
0
0
1
49603
49604
49605
49606
49607
49608
49609
49610
49611
49612
49614
49613
49615
49616
49617
49618
49619
49625
49620
49621
49622
49623
49624
49626
49627
1
17
11
4
49628
KCNH2
p.(His578-Arg582del) c.1732_1746del S5-pore-S6
KCNH2
p.(Met579Thr)
c.1736T>C
S5-pore-S6
missense
2
7
2
3
KCNH2
p.(Arg582Cys)
c.1744C>T
S5-pore-S6
missense
6
31
15
7
KCNH2
p.(Arg582Leu)
c.1745G>T
S5-pore-S6
missense
2
4
0
2
49629
49630
49631
49632
49633
49634
49635
49636
49637
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Gly584Ser)
p.(Gly584Cys)
p.(Gly584Val)
p.(Leu589Pro)
p.(Gly590Val)
p.(Gln592Argfs*2)
p.(Ile593Thr)
p.( Ile593Arg)
c.1750G>A
c.1750G>T
c.1751G>T
c.1766T>C
c.1769G>T
c.1775delA
c.1778T>C
c.1778T>G
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
Missense
missense
Missense
Missense
frameshift
Missense
Missense
1
1
1
1
1
1
1
1
8
6
2
3
3
5
4
2
2
2
1
2
2
0
3
0
4
1
0
0
0
3
0
1
KCNH2
p.(Lys595Glu)
c.1783A>G
S5-pore-S6
Missense
2
5
2
1
KCNH2
KCNH2
p.(Lys595Asn)
p.(Tyr597Cys)
c.1785A>T
c.1790A>G
S5-pore-S6
S5-pore-S6
Missense
missense
1
1
2
3
0
2
1
0
KCNH2
p.(Gly601Ser)
c.1801G>A
S5-pore-S6
missense
4
13
7
1
KCNH2
p.(Gly603Asp)
c.1808G>A
S5-pore-S6
missense
1
3
2
0
KCNH2
p.(Gly604Ser)
c.1810G>A
S5-pore-S6
missense
4
12
2
4
KCNH2
KCNH2
p.(Asp609Asn)
p.(Tyr611*)
c.1825G>A
c.1833T>G
S5-pore-S6
S5-pore-S6
missense
nonsense
1
1
7
3
2
2
3
0
KCNH2
p.(Thr613Met)
c.1838C>T
S5-pore-S6
missense
5
23
9
8
KCNH2
p.(Thr613Lys)
c.1838C>A
S5-pore-S6
missense
1
4
1
2
KCNH2
p.(Ala614Val)
c.1841C>T
S5-pore-S6
missense
4
11
6
1
KCNH2
KCNH2
p.(Leu615Phe)
p.(Thr618Ser)
c.1843C>T
c.1853C>G
S5-pore-S6
S5-pore-S6
missense
missense
1
1
2
2
1
1
0
0
49638
49639
49641
49640
49642
49643
49644
49645
49646
49647
49648
49649
49650
49651
49652
49653
49654
49655
49656
49657
49658
49659
49660
49661
49662
49663
49664
49665
49666
49667
49668
49669
49670
49671
49672
49673
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Ser621Arg)
p.(Ser621Asn)
p.(Leu622Phe)
p.(Thr623Ala)
p.(Thr623Ile)
p.(Val625Glu)
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
missense
missense
missense
missense
missense
1
1
1
1
1
1
4
2
2
2
2
3
2
1
0
1
1
1
0
0
1
0
0
1
49675
49674
49676
49677
49678
49679
S5-pore-S6
in-frame
insertion
1
5
0
4
49680
p.(Gly628Ser)
p.(Asn629Ser)
c.1861A>C
c.1862G>A
c.1864C>T
c.1867A>G
c.1868C>T
c.1874T>A
c.1878_1879ins
CCT ;1885_1941
dup
c.1882G>A
c.1886A>G
KCNH2
p.?
KCNH2
KCNH2
S5-pore-S6
S5-pore-S6
missense
missense
1
1
2
4
1
3
0
0
KCNH2
p.(Asn633Ser)
c.1898A>G
S5-pore-S6
missense
3
12
2
7
KCNH2
KCNH2
KCNH2
p.(Thr634Ala)
p.(Lys638Glu)
p.(Lys638Gln)
c.1900A>G
c.1912A>G
c.1912A>C
S5-pore-S6
S5-pore-S6
S5-pore-S6
1
1
1
2
2
5
1
0
4
0
1
0
KCNH2
p.(Lys638del)
1
2
0
1
49689
KCNH2
p.(Phe640del)
1
4
1
1
49690
KCNH2
KCNH2
KCNH2
KCNH2
p.(Ser641Phe)
p.(Val644Phe)
p.(Met645Leu)
p.(Ser649Pro)
S5-pore-S6
S5-pore-S6
S5-pore-S6
S5-pore-S6
missense
missense
missense
in-frame
deletion
in-frame
deletion
missense
missense
missense
missense
49681
49682
49683
49684
49685
49686
49687
49688
1
1
1
1
3
4
2
2
0
0
1
1
2
3
0
0
49691
49692
49693
49694
KCNH2
p.(Met651Valfs*3)
S5-pore-S6
frameshift
1
2
1
0
49695
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Gln664*)
p.(Ser668*)
Gly669Alafs*45
p.(Thr673*)
p.(Gln676*)
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
nonsense
nonsense
frameshift
nonsense
nonsense
1
1
1
1
1
3
2
2
2
3
0
1
0
1
2
2
0
1
0
0
49696
49697
49741
49698
49700
KCNH2
p.(Gln676Hisfs*46)
C-terminus
frameshift
1
2
1
0
49699
KCNH2
p.(Gln688*)
C-terminus
nonsense
1
18
8
7
49701
c.1913_1915del S5-pore-S6
c.1919_1921del
TCT
c.1922C>T
c.1930G>T
c.1933A>C
c.1945T>C
c.1951_1952del
AT
c.1990C>T
c.2003C>A
c.2006del
c.2019C>G
c.2026C>T
c.2028_2029del
AG
c.2062C>T
S5-pore-S6
KCNH2
p.(Glu698*)
c.2092G>T
C-terminus
nonsense
3
53
22
20
KCNH2
KCNH2
p.(Asp712Asn)
p.?
c.2134G>A
c.2145G>C
C-terminus
C-terminus
missense
splice site
1
1
2
3
1
0
0
2
KCNH2
p.0?
c.2146-2A>G
C-terminus
splice site
2
25
8
11
KCNH2
KCNH2
p.( Pro721Leu)
p.(Pro721Arg)
C-terminus
C-terminus
missense
missense
1
1
2
6
1
2
0
2
KCNH2
p.(Leu724Profs*10)
C-terminus
frameshift
1
3
0
2
49711
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(His731Pro)
p.(Leu732Pro)
p.(Gln738*)
p.(Arg744Pro)
p.(Arg752Trp)
p.(Arg752Pro)
p.(Ser783Pro)
p.(Gly785Ser)
p.(Gly785Alafs*25)
p.(Gly800Arg)
p.0?
p.0?
p.(Ala813Cysfs*17)
c.2162C>T
c.2162C>G
c.2169_2170du
p
c.2192A>C
c.2195T>C
c.2212C>T
c.2231G>C
c.2254C>T
c.2255G>C
c.2347T>C
c.2353G>A
c.2354delG
c.2398G>C
c.2399-2A>G
c.2401+1G>A
c.2436dupT
49702
49703
49704
49705
49706
49707
49708
49709
49710
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
missense
missense
nonsense
missense
missense
missense
missense
missense
frameshift
missense
splice site
splice site
frameshift
1
1
1
1
1
1
1
1
1
1
1
1
1
2
4
3
4
2
19
3
2
6
2
7
5
4
1
3
1
3
0
5
2
0
2
1
5
1
1
0
0
1
0
1
6
0
1
2
0
1
2
0
KCNH2
p.(Ser818Leu)
c.2453C>T
C-terminus
missense
3
6
3
0
KCNH2
KCNH2
KCNH2
KCNH2
p.(Val822Met)
p.(Arg823Gln)
p.(Arg823Trp)
p.(His831Pro)
c.2464G>A
c.2468G>A
c.2467C>T
c.2492A>C
C-terminus
C-terminus
C-terminus
C-terminus
missense
missense
missense
missense
1
1
1
1
4
2
3
4
3
1
2
0
0
0
0
3
KCNH2
p.(Asp837Asn)
c.2509G>A
C-terminus
missense
3
11
3
2
49712
49713
49714
49715
49717
49716
49718
49720
49719
49723
49721
49722
49724
49725
49726
49727
49730
49728
49729
49731
49732
49733
49734
KCNH2
KCNH2
p.(Met844_Ser1159d
c.2532_2535deli C-terminus
elinsIle)
nsTTAA
p.(Trp853Cysfs*15)
c.2559delG
C-terminus
C-terminus
1
6
0
4
49735
frameshift
1
4
1
1
nonsense
2
6
3
1
49736
49737
49738
nonsense
1
4
3
0
49740
missense
1
3
0
2
49739
frameshift
1
2
1
0
49742
frameshift
2
11
5
3
49743
49744
frameshift
1
4
0
3
49746
missense
1
3
2
0
49745
frameshift
1
3
1
1
49747
frameshift
2
5
3
0
49748
49751
frameshift
2
10
4
4
49749
49750
frameshift
1
3
2
0
49752
KCNH2
p.(Arg863*)
KCNH2
p.(Thr865*)
KCNH2
p.(Thr865Ile)
KCNH2
p.(Pro872Argfs*31)
KCNH2
p.(Gly873Alafs*5)
KCNH2
p.(Arg883Alafs*87)
KCNH2
p.(Arg883Gln)
KCNH2
p.(Arg912Alafs*63)
KCNH2
p.(Ala915Argfs*61)
KCNH2
p.(Arg912Glyfs*6)
KCNH2
p.(Gly925Valfs*49)
KCNH2
p.(Pro926Alafs*14)
c.2775dupG
C-terminus
frameshift
2
11
2
5
KCNH2
p.(Pro926Argfs*48)
c.2775delG
C-terminus
frameshift
1
6
4
0
KCNH2
p.(Trp927*)
c.2780G>A
C-terminus
nonsense
2
4
1
1
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Arg948His)
p.(Gly965Argfs*154)
p.(Leu973Argfs*84)
p.(Glu978Ter)
p.(Ser981Thrfs*76)
C-terminus
C-terminus
C-terminus
C-terminus
C-terminus
missense
frameshift
frameshift
nonsense
frameshift
1
1
1
1
1
6
2
2
2
3
5
0
0
0
2
0
1
1
1
0
C-terminus
frameshift
2
10
0
7
KCNH2
c.2587C>T
frameshift
c.2593_2599del
C-terminus
ACCACCA
c.2594C>T
C-terminus
c.2613_2669deli
C-terminus
nsACGCCTG
c.2616delC
C-terminus
c.2647_2659del
C-terminus
ACCACCA
c.2648G>A
C-terminus
c.2731_2732du
C-terminus
pGG
c.2734_2738du
C-terminus
p
c.2734_2738del
C-terminus
CGGGC
c.2774_2775del
C-terminus
GGinsT
c.2843G>A
c.2892dupC
c.2918delT
c.2932G>T
c.2942delG
c.2959_2960del
p.(Leu987Valfs*131)
CT
49754
49755
49753
49756
49757
49758
49759
49760
49761
49762
49763
49764
KCNH2
p.?
c.2966-3C>G
C-terminus
splice site
3
9
6
0
KCNH2
KCNH2
KCNH2
KCNH2
p.(Asn996Ile)
p.(Phe998Serfs*59)
p.(Trp1001*)
p.(Asp1003Thrfs*54)
C-terminus
C-terminus
C-terminus
C-terminus
missense
frameshift
nonsense
frameshift
1
1
1
1
2
3
2
5
1
0
0
4
0
2
1
0
KCNH2
p.(Arg1014Profs*39)
C-terminus
frameshift
1
16
4
10
49773
KCNH2
KCNH2
p.(Arg1014*)
p.(Ser1021Glnfs*98)
C-terminus
C-terminus
nonsense
frameshift
1
1
3
5
2
1
0
3
49774
49775
KCNH2
p.(Arg1032Alafs*21)
C-terminus
frameshift
1
3
2
0
49776
KCNH2
p.(Gly1031Profs*84)
c.2987A>T
c.2993delT
c.3002G>A
c. 3007delG
c.3036_3048del
CCCTCGATGCCC
C
c.3040C>T
c.3060dupC
c.3090_3102del
GGGTCGGCGGC
CC
c.3091_3101del
GGTCGGCGGCC
49765
49766
49767
49768
49769
49770
49771
C-terminus
frameshift
1
2
1
0
49777
KCNH2
p.(Arg1032Serfs*87)
c.3092dupG
C-terminus
frameshift
2
4
1
1
KCNH2
KCNH2
KCNH2
p.(Pro1034Glyfs*80) c.3093_3106del C-terminus
p.(Arg1032Glyfs*80) c.3094_3113del C-terminus
p.(Pro1034Glyfs*80) c.3096_3109del C-terminus
c.3096_3097ins
p.(Arg1033Alafs*26)
C-terminus
GCGGG
p.(Arg1035Glyfs*22)
c.3103delC
C-terminus
p.(Arg1035Glyfs*76) c.3103_3125del C-terminus
c.3104_3105ins
p.(Gly1036Argfs*22)
C-terminus
CC
p.(Gly1036Asp)
c.3107G>A
C-terminus
p.(Asp1037Argfs*82)
c.3107dupG C-terminus
c.3113delinsGG
p.(Val1038Glyfs*24) TCGGCGGCCCC C-terminus
GG
c.3190_3199del
p.(Leu1064Tyrfs*5)
C-terminus
CTGCAGCTGC
frameshift
frameshift
frameshift
1
1
1
2
3
2
0
2
1
1
0
0
49778
49779
49782
49780
49781
frameshift
1
4
1
2
49783
frameshift
frameshift
1
1
3
4
0
0
2
3
49772
49784
frameshift
1
3
2
0
49785
missense
frameshift
1
1
4
4
1
2
2
1
49786
49787
frameshift
1
5
4
0
49788
frameshift
1
3
0
2
49789
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
KCNH2
p.(Gly1085Hisfs*30)
KCNH2
KCNH2
KCNH2
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
SCN5A
p.(Pro1093Leu)
p.0?
p.(Ala1144Thr)
p.(Arg18Gln)
p.0?
p.(Val411Met)
p.(Gly615Glu)
p.(Pro701Leu)
p.(Gly797Val)
p.(Arg814Gln)
p.(Arg975Trp)
p.(Glu1032Lys)
p.(Gln1033Arg)
p.(Ser1079Phe)
p.(Trp1095Cys)
p.(Asp1114Glu)
p.(Ala1186Thr)
p.(Ala1221Val)
p.(Ile1278Asn)
p.(Thr1304Met)
c.3252_3262del
GGGGCCTGGCC
c.3278C>T
c.3330+1G>A
c.3430G>A
c.53G>A
c.703+1G>A
c.1231G>A
c.1844G>A
c.2102C>T
c.2390G>T
c.2441G>A
c.2923C>T
c.3094G>A
c.3098A>G
c.3236C>T
c.3285G>T
c.3342C>A
c.3556G>A
c.3662C>T
c.3833T>A
c.3911C>T
SCN5A
p.(Ala1330Thr)
c.3988G>A
C-terminus
frameshift
1
2
0
1
49790
C-terminus
C-terminus
C-terminus
N-terminus
DI
DI
DI-DII
DI-DII
DII
DII
DII-DIII
DII-DIII
DII-DIII
DII-DIII
DII-DIII
DII-DIII
DII-DIII
DIII
DIII
DIII
missense
splice site
missense
missense
splice site
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
missense
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
4
2
4
2
6
2
2
3
3
2
2
2
3
2
9
2
2
2
4
0
2
0
1
0
0
0
1
0
2
1
1
1
0
0
2
1
1
1
2
1
0
1
2
1
5
1
0
2
0
0
0
0
2
1
4
0
0
0
0
DIII
missense
2
7
5
0
49791
49792
49793
47469
47470
47471
47336
47337
47338
47339
47476
47477
47478
47479
47480
47481
47482
47483
47484
47485
47486
49027
1
3
0
2
2
6
3
1
1
1
1
2
16
4
0
9
0
1
2
3
6
27
8
10
SCN5A
p.(Phe1617del)
SCN5A
SCN5A
SCN5A
p.(Thr1620Met)
p.(Arg1644His)
p.(Ala1746Thr)
c.4859C>T
c.4931G>A
c.5236G>A
DIV
DIV
DIV
in-frame
deletion
in-frame
deletion
missense
missense
missense
SCN5A
p.(Ile1768Val)
c.5302A>G
C-terminus
missense
SCN5A
p.(Gln1507_Pro1509 c.4519_4527del
DIII-DIV
del)
CAGAAGCCC
c.4850_4852del DIV
47487
47488
49028
47489
47490
47491
47492
49029
49030
49031
SCN5A
p.(Glu1784Lys)
c.5350G>A
C-terminus
missense
13
34
15
5
SCN5A
p.(Asp1790Gly)
c.5369A>G
C-terminus
missense
1
14
9
3
p.(Tyr1795_Glu1796i c.5385_5387du
C-terminus
nsAsp)
pTGA
in-frame
insertion
23
134
62
49
SCN5A
49032
49033
47493
49034
49035
49036
49037
49038
49039
49040
49041
49042
49043
49044
49045
47494
47340
47342
47343
47472
47473
47474
47475
47495
49046
49047
49048
49049
49050
49051
49052
49053
49054
49055
49056
49057
59058
49059
49060
Supplemental Table 2. KCNH2 and SCN5A variants by location, type of variant and parental transmission: Genetic alterations of the amino acid sequence
were characterized by location in the channel protein, by the type of variant (missense, splice site, in-frame insertions/deletions, nonsense, and frameshift). For
KCNH2 variants, the nucleotide and amino acid designations were based on the reference sequences NM_000238.3 and NG_008916.1. Exons are numbered
like in Splawski et al. 1998, Genomics 51, 86-97. KCNH2 variants were categorized by their location in the encoded channel as follows: variants in the
transmembrane region, either in S1-S4 or in S5-pore-S6 defined as amino acid residues from 398 to 551 and 552 to 657; in the remaining N-terminus region,
defined as amino acid residues before 398, and the C-terminus region, defined as after residue 657. For SCN5A variants, the nucleotide and amino acid
designations were based on the SCN5A sequences NM_198056.2 and NG_008934.1. Exons are numbered like in Wang et al. 1996, Genomics 34:9-16. The
variants were categorized by their location in the encoded channel as follows: variants in one of the four transmembrane domains, defined as amino acid
residues from 127 to 415 (DI), 712 to 939 (DII), 1201 to 1470 (DIII) and 1524 to 1772 (D4); in the linkers between two domains; in the N-terminus region,
defined as amino acid residues before 126, and the C-terminus region, defined as residues 1773 to 2016.
Supplemental Table 3. The grandparental origin of KCNQ1 alleles in CEPH families
Supplemental Table 3. The grandparental origin of KCNQ1 alleles in CEPH families: The transmission of the grandparental alleles to grandchildren was
determined after studying the intragenic microsatellite D11S4088 if not available on the CEPH database, and D11S1318 when more informativity was required
to trace the four grandparental alleles. ‘Other markers’ corresponds to additional intragenic markers (rs231352, rs86392 and rs1079714), or D11S4146 for one
family. + : yes, - : no, GM: grandmother, GF: grandfather.
Supplemental Table 4. The grandparental origin of KCNH2 alleles in CEPH families
Supplemental Table 4. The grandparental origin of KCNH2 alleles in CEPH families: The transmission of the grandparental alleles to grandchildren was
determined after haplotyping markers flanking KCNH2 gene and available on the CEPH database, especially D7S1805 or D7S1826, and we genotyped
D7S2461 when more informativity was required to trace the four grandparental alleles. All the markers used were the following rs740136, rs757723,
rs2040906, D7S1805, D7S1826 - KCNH2 - NOS3, D7S636, D7S642, D7S2461, rs875588, rs2014611, rs880310, rs38993. . + : yes, - : no, GM: grandmother,
GF: grandfather.
Supplemental Table 5. The grandparental origin of SCN5A alleles in CEPH families
Supplemental Table 5. The grandparental origin of SCN5A alleles in CEPH families: The transmission of the grandparental alleles to grandchildren was
determined after genotyping (D3S1260, D3S3521) and haplotyping several microsatellites flanking SCN5A (D3S3639, D3S1260 –SCN5A – D3S1000, D3S3521)
(D3S1260, D3S3521) . . + : yes, - : no, GM: grandmother, GF: grandfather.
Supplemental Table 6. Grandparental origin of KCNQ1 alleles in CEPH families
Family
number
Sib
number
Maternal
GM
Maternal
GF
Paternal
GM
Paternal
GF
P value
Naumova et al.
31
519
130
0.25
126
0.24
149
0.29
114
0.22
0.18
All sibs
43
712
182
0.26
179
0.25
193
0.27
158
0.22
0.30
Sibs with full
informativity
40
688
177
0.26
167
0.24
189
0.27
155
0.23
0.30
Supplemental Table 6. Grandparental origin of KCNQ1 alleles in CEPH families: Grandparental origin of KCNQ1 alleles was determined as shown in
Supplemental Figure 1. Are given the data and statistical analyses performed on the 31 families studied in Naumowa et al. 2001 report, on 43 families, and on
40 families after exclusion of three families since the origin of the four grandparental alleles could not be determined. P value when the ratio of each category
could be assumed to 0.25 by Chi-square test (uniform distribution).
Supplemental Table 7. Parental transmission of LQTS alleles according to LQTS genes, gender and countries
Total
France
p
value
n
(%)
248
164/84
93/47
71/37
(66)
(66)
(66)
<0.0001
0.0001
0.0011
0.90
LQT2, total transmission
Maternal/Paternal transmission to all probands
Maternal/Paternal transmission to females
Maternal/Paternal transmission to males
Transmission between females and males
195
109/86
74/57
35/29
(56)
(56)
(55)
0.10
0.13
0.45
0.81
LQT3, total transmission
Maternal/Paternal transmission to all probands
Maternal/Paternal transmission to females
Maternal/Paternal transmission to males
Transmission between females and males
36
19/17
8/7
11/10
(53)
(53)
(52)
0.73
0.79
0.83
0.95
910
602/308
335/168
267/140
(66)
(67)
(66)
<0.0001
<0.0001
<0.0001
0.75
763
428/335
247/182
181/153
(56)
(58)
(54)
0.0008
0.0017
0.12
0.35
Transmission to probands
LQT1, total transmission
Maternal/Paternal transmission to all probands
Maternal/Paternal transmission to females
Maternal/Paternal transmission to males
Transmission between females and males
Transmission to all carriers
LQT1, total transmission
Maternal/Paternal transmission to all carriers
Maternal/Paternal transmission to females
Maternal/Paternal transmission to males
Transmission between female and male carriers
LQT2, total transmission
Maternal/Paternal transmission to all carriers
Maternal/Paternal transmission to females
Maternal/Paternal transmission to males
Transmission between female and male carriers
Germany
p
value
n
(%)
93
65/28
29/15
36/13
(71)
(66)
(73)
<0.0001
0.034
0.0010
0.42
40
20/20
16/11
4/9
(50)
(59)
(31)
1
0.33
0.26
0.18
(100)
(100)
(100)
NA
NA
NA
NA
394
255/139
139/75
116/64
(65)
(65)
(64)
<0.0001
<0.0001
=0.0001
0.91
194
119/75
68/38
51/37
(61)
(64)
(58)
0.0016
0.0036
0.13
0.37
5
5/0
1/0
4/0
p
value
n
(%)
47
32/15
16/7
16/8
(68)
(70)
(67)
0.013
0.06
0.10
1
43
28/15
19/11
9/4
(65)
(63)
(69)
0.047
0.14
0.16
1
6
4/2
3/1
1/1
(67)
(75)
(50)
NA
NA
NA
NA
207
149/58
79/31
70/27
(72)
(72)
(72)
<0.0001
<0.0001
<0.0001
0.95
210
112/98
71/46
41/52
(53)
(61)
(44)
0.33
0.021
0.25
0.017
Netherlands
p
n (%) value
16
11/5
8/2
3/3
(69)
(80)
(50)
0.21
0.10
1
0.29
22
12/10
8/6
4/4
(55)
(57)
(50)
0.66
0.59
1
1
20
9/11
4/5
5/6
(45)
(44)
(45)
0.65
NA
NA
NA
107
62/45
37/21
25/24
(58)
(64)
(51)
0.10
0.036
0.88
0.18
182
91/91
49/54
42/37
(50)
(48)
(53)
1
0.62
0.57
0.45
Japan
p
value
p value
among
countries
n
(%)
92
56/36
40/23
16/13
(61)
(63)
(55)
0.037
0.032
0.57
0.44
0.60
0.79
0.31
90
49/41
31/29
18/12
(54)
(52)
(60)
0.39
0.79
0.27
0.45
0.54
0.74
0.21
5
1/4
0/1
1/3
(20)
( 0)
(25)
NA
NA
NA
NA
0.37
NA
NA
202
136/66
80/41
56/25
(67)
(66)
(69)
<0.0001
0.0004
0.0006
0.65
0.077
0.60
0.071
177
106/71
59/44
47/27
(60)
(57)
(64)
0.0085
0.13
0.020
0.40
0.085
0.087
0.073
LQT3, total transmission
219
19
19
167
14
Maternal/Paternal transmission to all carriers
125/94 (57) 0.036
14/5 (74)
0.06
14/5 (74) 0.06
92/75 (55) 0.18
5/9 (36)
0.42
0.070
Maternal/Paternal transmission to females
63/43 (59) 0.052
5/2 (71)
0.45
10/2 (83) 0.04
46/35 (57) 0.22
2/4 (33)
0.68
0.16
Maternal/Paternal transmission to males
62/51 (55) 0.30
9/3 (75)
0.14
4/3 (57) 1
46/40 (53) 0.51
3/5 (38)
0.72
0.40
Transmission between female and male carriers
0.58
NA
NA
NA
NA
p value when the ratio of each transmission could be assumed to 0.5. % = maternal transmission of all transmissions. NA = not available due to small numbers. Transmission ratio between females and
males were compared and P values were given.
Supplemental Table 8. Grandparental transmission in control and LQTS families
Total alleles, n
KCNQ1
All sibs
CEPH
LQT1 families
female
CEPH
LQT1 families
male
CEPH
LQT1 families
KCNH2
All sibs
CEPH
LQT2 families
female
CEPH
LQT2 families
male
CEPH
LQT2 families
Maternal
Grandmother,
Grandfather,
n(%)
n(%)
Paternal
Grandmother,
Grandfather,
n(%)
n(%)
p value(1)
p value(2)
688
290
177 (26)
112 (39)
167
89
(24)
(30)
189
52
(27)
(18)
155 (23)
37 (13)
0.30
<0.0001
<0.0001
332
152
91 (27)
60 (39)
75
47
(23)
(31)
88
32
(27)
(21)
78 (23)
13 ( 9)
0.54
<0.0001
0.0001
356
138
86 (24)
52 (38)
92
42
(26)
(30)
101
20
(28)
(15)
77 (22)
24 (17)
0.32
0.0002
0.0011
670
242
174 (26)
84 (35)
161
62
(24)
(26)
170
52
(25)
(21)
165 (25)
44 (18)
0.90
0.0019
0.025
340
127
88 (26)
47 (37)
82
33
(24)
(26)
89
29
(26)
(23)
81 (24)
18 (14)
0.90
0.0036
0.036
330
115
86 (26)
37 (32)
79
29
(24)
(25)
81
23
(25)
(20)
84 (25)
26 (23)
0.95
0.28
0.52
SCN5A
All sibs
CEPH
546
133 (24)
140 (26)
146 (27)
127 (23)
0.68
0.25
LQT3 families
87
30 (34)
20 (23)
19 (22)
18 (21)
0.23
female
CEPH
268
63 (24)
71 (26)
71 (26)
63 (24)
0.81
0.82
LQT3 families
37
11 (30)
9 (24)
8 (22)
9 (24)
0.93
male
CEPH
278
70 (25)
69 (25)
75 (27)
64 (23)
0.83
0.31
LQT3 families
50
19 (38)
11 (22)
11 (22)
9 (18)
0.2
(1) p value when the ratio of each category could be assumed to 0.25 (uniform distribution). (2) p value between LQTS and CEPH. In this table, only
grandparental control alleles for CEPH families in which the four grandparental alleles were traced were given. Nevertheless we found similar data when
all the 2025 genotyped alleles were analyzed.
.
Supplemental Table 9. Clinical characteristics of Japanese LQT1 corresponding to parental gender
symptomatic patients/available sibs (%)
Patients with QTc >440ms/available sibs
mean QTc ± SD (ms)
maternal descendents
paternal descendents
p value
40/129 (31%)
112/126 (89%)
477±41
24/65 (37%)
48/59 (81%)
471±41
0.42
0.17
0.7
symptomatic patient = syncope, torsade de pointes, cardiac arrest or sudden death.
Supplemental Table 10. Descendants in full genotyped families corresponding to each country
Maternal transmission
Paternal transmission
carriers, n
total female male
noncarrier, n
total female male
LQT1
All
France
Germany
Netherlands
Japan
364
174
103
39
48
197
103
55
18
21
167
71
48
21
27
203
106
59
14
24
106
54
37
5
10
97
52
22
9
14
364/567
174/ 280
103/162
39/53
48/72
(64)
(62)
(64)
(74)
(67)
LQT2
All
France
Germany
Netherlands
Japan
268
81
70
68
49
144
39
44
34
27
124
42
26
34
22
198
59
58
57
24
107
39
28
28
12
91
20
30
29
12
268/466
81/140
70/128
68/125
49/73
(58)
(58)
(55)
(54)
(67)
carriers/total
descendants (%)
carriers, n
total female male
noncarrier, n
total female male
<0.0001
<0.0001
0.0005
0.0006
0.0047
175
94
28
33
20
96
52
15
16
13
79
42
13
17
7
158
89
21
28
20
68
35
13
14
6
90
54
8
14
14
175/333
94/183
28/49
33/61
20/40
0.0012
0.06
0.29
0.33
0.0034
198
44
67
62
25
91
19
27
33
12
107
25
40
29
13
140
45
45
37
13
65
19
20
19
7
75
26
25
18
6
198/338
44/89
67/112
62/99
25/38
p
value(1)
p
value(1)
p
value(2)
(53)
(51)
(57)
(54)
(50)
0.35
0.71
0.32
0.52
1.
0.0006
0.021
0.42
0.03
0.08
(59)
(49)
(60)
(63)
(66)
0.0016
0.92
0.038
0.012
0.052
0.76
0.21
0.42
0.22
0.89
(56)
(100)
(80)
(55)
NA
0.17
0.16
0.18
0.34
NA
0.86
0.15
0.1
0.32
NA
carrier/total
descendants (%)
LQT3
All
92
45
47
68
32
36
92/160 (58) 0.0588
66
32
34
51
23
28
66/117
France
4
1
3
5
3
2
4/9 (44) 0.74
2
1
1
0
0
0
2/2
Germany
7
4
3
11
4
7
7/18 (39) 0.35
4
1
3
1
0
1
4/5
Netherlands 81
40
41
52
25
27
81/133 (61) 0.012
60
30
30
50
23
27
60/110
Japan
0
0
0
0
0
0
NA NA NA
0
0
0
0
0
0
NA
(1) Chi-square test when compared with a carrier ratio assumed to be of 0.5. (2) Chi-square test when compared with carrier ratios in maternal transmission.