Table 1 (a/b) Whole exome sequencing (WES) was performed in 16 individuals with SUD. The age of the individuals at the SUD event and the eleven potentially causative variants after stringent filtering process, name of the gene, OMIM, Reference Sequence (NM_number) of the gene, variant, amino acid (AA) change, variant type (splice_donor, splice_acceptor, missense), human phenotype ontology (HPO) match, population frequency (GnomAD), Single Nucleotide Polymorphism database number (dbSNP), MetaLR logistic regression (LR)-based score (MetaLrRank), ACMG criteria and classification are listed. Evidence of pathogenicity of each variant was shown. Pathogenic criteria: PVS1 (very strong), PM2 (moderate), PS3 (strong), PP3, PP4 (supporting). Evidence of benign impact: BS1 (strong). The variants were deposited and made publicly available at LOVD v.3.0 (Leiden Open Variation Database), LOVD variant link is listed

(a) List of identified variants after the described filter setting and HPO annotation

8 months

DSG2

125671

NM_001943.4

c.81+1G>C

p.(?)

Splice donor

Sudden cardiac death

–

–

–

PVS1-m, PM2

3

Individual #00329013 - Global Variome shared LOVD

3 months

UPB1

606673

NM_016327.2

c.917-1G>A

p.(?)

Splice acceptor

Status epilepticus

0.0017889

143493067

–

PVS1, PM2

4

Individual #00329092 - Global Variome shared LOVD

4 weeks

SCN4A

603967

NM_000334.4

c.787G>A

p.(Val263Ile)

Missense

Arrhythmia, Apnea

0.0000121

–

0.97394

PM1, PM2, PP3

3

Individual #00329093 - Global Variome shared LOVD

3 months

RYR2

180902

NM_001035.2

c.1939C>T

p.(Arg647Cys)

Missense

Sudden cardiac death

0.0001465

202040519

0.96504

PM2, PP3

3

Individual #00329094 - Global Variome shared LOVD

SCN8A

600702

NM_014191.3

c.5392G>A

p.(Asp1798Asn)

Missense

Status epilepticus

–

–

0.92015

PM2, PP2

3

Individual #00329094 - Global Variome shared LOVD

9 months

AKAP9

604001

NM_005751.4

c.7096A>G

p.(Ile2366Val)

Missense

Sudden cardiac death

0.0000248

368823780

0.08032

PM2, BP4

3

Individual #00329095 - Global Variome shared LOVD

5 weeks

SCN5A

600163

NM_198056.2

c.3520C>T

p.(Arg1174Trp)

Missense

Arrhythmia, sudden cardiac death

0.0000348

367906630

0.9016

PM2, PP2, PP3

3

Individual #00329096 - Global Variome shared LOVD

28 years

DTNA

601239

NM_001390.4

c.1571G>A

p.(Arg524His)

Missense

Sudden cardiac death

0.0000906

142108185

0.50319

PP3, BS2

3

Individual #00329097 - Global Variome shared LOVD

32 years

RAF1

164760

NM_002880.3

c.1334T>G

p.(Leu445Arg)

Missense

Arrhythmia

0.0000239

–

0.95649

PM1, PP2, PP3, BS2

3

Individual #00329098 - Global Variome shared LOVD

23 years

SCN5A

600163

NM_198056.2

c.3152T>C

p.(Val1051Ala)

Missense

Arrhythmia, sudden cardiac death

0.000004

–

0.83793

PM2

3

Individual #00329099 - Global Variome shared LOVD

RBM20

613171

NM_001134363.2

c.215A>T

p.(Asn72Ile)

Missense

Sudden cardiac death

–

–

0.80363

PM2

3

Individual #00329099 - Global Variome shared LOVD

(b) List of additionally identified variants by the sudden death-gene panel

12 weeks

CTNNA3

607667

NM_013266.3

c.935C>T

p.(Ala312Val)

Missense

No

0.00002830

–

0.62663

PM2

3

Individual #00329100 - Global Variome shared LOVD

4 weeks

KCNA5

176267

NM_002234.3

c.98A>T

p.(Glu33Val)

Missense

No

0.0002093

71584818

0.93829

PM2, PP3

3

Individual #00329093 - Global Variome shared LOVD