1

SUPPLEMENTAL MATERIAL: 4 TABLES, 1 FIGURE and ACKNOWLEDGMENTS

Supplemental Table 1: List of participating centers

Country / Center / No Patients (%)
France / Multiple / 130 (19.2)
Japan / Multiple / 119 (17.5)
Italy / Multiple / 84 (12.4)
South Korea / Multiple / 79 (11.6)
Belgium / Multiple / 48(7)
Taiwan / Single / 40 (5.9)
Spain / Multiple / 35(5.2)
Netherlands / Single / 32(4.7)
Israel / Multiple / 32(4.7)
China / Multiple / 25(3.7)
UK / Single / 20(3)
Germany / Single / 17(2.5)
Denmark / Single / 10(1.5)
Canada / Single / 7(1.1)

Supplemental Table 2. List of all SCN5A mutations.

Scn5A mutation subtype
Frequency / Percent
Unknown / 16 / 11
E1784K / 4 / 2.7
Missense / 4 / 2.7
c.2780A>G (p.Asn927Ser) / 2 / 1.4
c．827 T＞A p．L276Q / 2 / 1.4
D356N (p.Asp356Asn) / 2 / 1.4
Exon 28 ; 5228 G>A ; G1743E ; Missense ; DIV-S5/S6 and Exon 21 ; 3727 G>A ; D1243N* ; Missense ;DIII-S2 / 2 / 1.4
L276Q (p.Leu276Gln) / 2 / 1.4
SCN5A p.1645T>M, SCN5A c.393-5C>A / 2 / 1.4
W1412X (p.Trp1421*) / 2 / 1.4
(Ht) R1919C / 1 / 0.7
3917G>A; p.(Arg1306His) / 1 / 0.7
5350G>A; E1784K / 1 / 0.7
A1698T / 1 / 0.7
AKAP9: c.2581T>C (p.Tyr861His); NEXN: c.1453G>A (p.Glu485Lys) / 1 / 0.7
c. 1063 T > A; p. Phe 355 Ile; exon 9 / 1 / 0.7
c. 1100G>A p. R367H / 1 / 0.7
c. 1895 C > T; p. Thr 632 Met; exon 13 / 1 / 0.7
c. 2204C>T p. A735V / 1 / 0.7
c. 3823G>A pAsp1275Asn / 1 / 0.7
c. 4294 A > G; p.Arg 1432 Gly; exon 24 / 1 / 0.7
c. 4426 C > T; p. Gln 1476 X; exon 25 / 1 / 0.7
c. del T 2850 ; p. Pro 951 fsX 956; exon 17 / 1 / 0.7
c.[2632C>T]+[=] (p.[R878C]+[=]) / 1 / 0.7
c.[4300-2A>t]+[=] / 1 / 0.7
c.[5189C>A]+[=] (p.Pro1730His) / 1 / 0.7
c.1038GT p.Glu346stop / 1 / 0.7
c.1051G>T p.Gly351Cys ex9 / 1 / 0.7
c.1066G>A p.Asp356Asn ex9 / 1 / 0.7
c.1126G>T (p.Arg376Cys) / 1 / 0.7
c．1127 G＞A p．R376H / 1 / 0.7
c.1673 A>G p.H558R / 1 / 0.7
c.1844G>A p.Gly615Glu ex12 + c.4247C>A p.Ala1416Glu ex24 / 1 / 0.7
c.2200A>G p.Met 734Val ex14 / 1 / 0.7
c.2204C>T p.Ala735Val ex14 / 1 / 0.7
c.2441 G>A p.R814Q / 1 / 0.7
c.250G>A p.Asp84Asn ex2 / 1 / 0.7
c.2583_2583delTT (p.Phe861TrpfsX90) / 1 / 0.7
c.2633G>T p.Arg878Leu ex16 / 1 / 0.7
c.2635T>C (p.Trp879Arg) / 1 / 0.7
c.2689G>A p.Gly897Arg ex16 / 1 / 0.7
c.2729C>T, p.Ser910Leu / 1 / 0.7
c.3040 C>T p.P1014S / 1 / 0.7
c.311G>A p.R104Q / 1 / 0.7
c.3236C>A p.Ser1079Tyr ex18 / 1 / 0.7
c.3316delG, p.Ala1106Profs*39 / 1 / 0.7
c.3477delT in exon 19 / 1 / 0.7
c.3512-2A>C / 1 / 0.7
c.3673G>A p.Glu1225Lys ex21 / 1 / 0.7
c.3694C>T p.Arg1232Trp ex21 / 1 / 0.7
c.3727G>A (p.Asp1243Asn) + c.5228G>A (p.Gly1743Glu) / 1 / 0.7
c.3840+1G>A / 1 / 0.7
c.3956G>T (p.Gly1319Val) / 1 / 0.7
c.4259 A > G; p. Gly 1420 Asp; exon 24 / 1 / 0.7
c.4299+1delG ex24 / 1 / 0.7
c.4346A>G p.Tyr449Cys / 1 / 0.7
c.4573 G > A; p. Val 1525 Met: exon 27 / 1 / 0.7
c.4573G>A p.Val1525Met ex27 / 1 / 0.7
c.4642 Q > A; p. Glu 1548 Lys; exon 27 / 1 / 0.7
c.4642G>A p.Glu1548Lys ex27 / 1 / 0.7
c.4642G>A p.Glu1548Lys ex28 / 1 / 0.7
c.4813+6_4819+9dupGGGT / 1 / 0.7
c.4838A>T p.Gln1613Leu ex28 / 1 / 0.7
c.4894C>T p.Arg1632Cys ex28 / 1 / 0.7
c.4912C>T (p.Arg1638X) / 1 / 0.7
c.4912C>T p.Arg1638X ex28 + c.3603C>G p.Ile1201Met ex20 / 1 / 0.7
c.4981G>A p.Gly1661Arg ex28 / 1 / 0.7
c.5083C>T p.Gln1695X ex28 / 1 / 0.7
c．5126 C＞T p．T1709M / 1 / 0.7
c.5183G>A p.Cys1728Tyr ex28b / 1 / 0.7
c.5265_5270del insA p.Tyr1755* ex28 / 1 / 0.7
c.530T>C, p.Leu177Pro / 1 / 0.7
c.5689C>T (p.Arg1897Trp) (+ DPP6 (chr 7q36) haplotype) / 1 / 0.7
c.611+1G>A, p.? / 1 / 0.7
c.655C>T, p.Arg219Cys / 1 / 0.7
c.664C>T p.Arg222* ex6 / 1 / 0.7
c.664C>T p.Arg222X ex6 / 1 / 0.7
c.688A>G, p.Ile230Val / 1 / 0.7
c.del T 2850; p. Pro 951fsX 956; exon 17 / 1 / 0.7
D1243N / 1 / 0.7
D1819N / 1 / 0.7
D356N point mutation / 1 / 0.7
E901K / 1 / 0.7
E901K G2701A / 1 / 0.7
ex14 c.2077 C>T p.R693C / 1 / 0.7
exon 16 ; c.2729C>T ; p.Ser910Leu / 1 / 0.7
Exon 27 ; 4642 G>A; E1548K* Missense DIV-S1/S2 / 1 / 0.7
F1775fsX1785 / 1 / 0.7
Frameshift / 1 / 0.7
g.38601661C>T / 1 / 0.7
g.38674796C>T ; c.3G>A / 1 / 0.7
G35S / 1 / 0.7
heterozygous in SCN5A defined as c.4437+5G A / 1 / 0.7
Intron 7 ; 934 +1 G>A*; Splice site ; DI-S5/S6 / 1 / 0.7
IVS22+2T>C T3963+2C / 1 / 0.7
p.Gly1935Ser (c.5803G>A) / 1 / 0.7
point mutation / 1 / 0.7
point mutation (missense mutation) [de novo mutation: c.1235T>A, p. V412D] / 1 / 0.7
point mutation (missense mutation) [de novo mutation: c.1685A>G, p.H558R] / 1 / 0.7
point mutation (missense mutation) [de novo mutation: c.4886 G>A, p.R1629Q] / 1 / 0.7
point mutation (missense mutation) [de novo mutation: c.5262G>A, p.D1690N] / 1 / 0.7
R104Q (c.311G>A) / 1 / 0.7
R121W / 1 / 0.7
r1512w amminoacidic substitution / 1 / 0.7
R4867delC / 1 / 0.7
R814Q / 1 / 0.7
SCN5A / c.1288A>G (p.Lys430Glu) / 1 / 0.7
SCN5A / c.1336G>A (pGlu446Lys) / 1 / 0.7
SCN5A / c.1603C>T (p.Arg535*) / 1 / 0.7
SCN5A / c.2423G>C (p.Arg808Pro) / 1 / 0.7
SCN5A / c.3334C>T p.Gln1112X) / 1 / 0.7
SCN5A / c.4216G>C (p.Gly1406Arg) / 1 / 0.7
SCN5A / c.4387A>T (p.Asn1463Tyr) / 1 / 0.7
SCN5A / c.4895G>T / 1 / 0.7
SCN5A / c.5228G>A (p.Gly1743Glu) / 1 / 0.7
T1304M / 1 / 0.7
T220I / 1 / 0.7
T3963+2C / 1 / 0.7

Supplemental Table 3. Comparison between subgroups B1+B2 and B3.

B1 + B2 / B3 / P value
Number of patients / 189 / 63
Patient Age at AE (year) / All patients / 46.0±12.7 / 46.5±15.0 / 0.820
< 16 years / 1(1) / 3 (5)
16-70 / 186 (98) / 59 (94) / 0.044
>70 years / 2 (1) / 1 (2)
Gender
Male / 174 (92) / 55 (87) / 0.256
Female / 15 (8) / 8 (13)
M/F ratio / 11.6 / 6.9
Ethnicity
Caucasian / 120 (63) / 40 (63) / 0.914
Asian / 59 (31) / 19 (30)
Other/Unknown / 10 (5) / 4 (6)
Proband Status
Proband / 147 (78) / 39 (62) / 0.132
Not Proband / 33 (17) / 15 (24)
Unknown / 9 (5) / 9 (14) / 0.020
Family history of SCD
Yes / 53 (28) / 19 (30) / 0.360
No / 121 (64) / 32 (51)
Unknown / 15 (8) / 12 (19) / 0.014
History of syncope
Yes / 132 (70) / 27 (43) / <0.001
No / 57 (30) / 36 (57)
Spontaneous type 1-ECG
Yes / 149 (79) / 26 (41) / <0.001
No / 40 (21) / 37 (59)
VF inducibility
EPS performed / 167 (88) / 33 (52) / <0.001
Yes / 144 (86) / 0 (0) / <0.001
No / 23 (14) / 33 (100)
Presence of SCN5A mutation
Testing done / 124 (66) / 44 (70) / 0.537
Yes / 40 (32) / 21 (48) / 0.067
No / 84 (68) / 23 (52)

Supplemental Table 4: Logistic regression analysis of group B3 characteristics. No single parameter identified group B3 patients.

Parameter / OR [95% CI] / p-value
Female Gender / 1.92 [0.65-5.65] / 0.233
Asian Ethnicity / 0.80 [0.32-2.04] / 0.643
Family history of SCD / 0.79 [0.34-1.81] / 0.568
SCN5A mutation / 1.67 [0.76-3.61] / 0.204
Age of first AE / 1.02 [0.99-1.05] / 0.243
Proband / 0.79 [0.30-2.05] / 0.623

Supplemental Figure 1: Distribution of SCN5A mutation by pathogenicity. Most of the SCN5A mutations were identified as pathogenic (56.34%) and likely pathogenic (23.24%).

Acknowledgments: The authors thank Aurelie Thollet, PharmD PhD (Institut du Thorax, Service de Cardiologie, CHU de Nantes, Nantes, France), Jaime Hernandez, MD (Hospital Clínic de Barcelona, Spain), Sergi Cesar, MD (Hospital Sant Joan de Déu, Barcelona, Spain), Giuseppe Allocca, MD (Hospital of Conegliano, Conegliano, Italy), CamillaHelene Bang Jespersen, MD (Copenhagen University Hospital, Denmark) and Rami Fogelman, MD (Schneider Medical Center, Israel) for their cooperation in collecting the data.