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. Author manuscript; available in PMC: 2011 Jan 1.
Published in final edited form as: Heart Rhythm. 2009 Oct 8;7(1):33–46. doi: 10.1016/j.hrthm.2009.09.069

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

Jamie D Kapplinger *,1, David J Tester *,1, Marielle Alders †, Begoña Benito ‡, Myriam Berthet §,∥, Josep Brugada , Pedro Brugada #, Véronique Fressart §,∥,**, Alejandra Guerchicoff ††, Carole Harris-Kerr ‡‡, Shiro Kamakura §§, Florence Kyndt ∥∥,¶¶,##, Tamara T Koopmann ***, Yoshihiro Miyamoto †††, Ryan Pfeiffer ††, Guido D Pollevick ‡‡, Vincent Probst ∥∥,##, Sven Zumhagen ‡‡‡, Matteo Vatta §§§, Jeffrey A Towbin ∥∥∥, Wataru Shimizu §§, Eric Schulze-Bahr ‡‡‡, Charles Antzelevitch ††, Benjamin A Salisbury ‡‡, Pascale Guicheney §,∥,**, Arthur A M Wilde ***, Ramon Brugada ¶¶¶, Jean-Jacques Schott ∥∥,¶¶,###, Michael J Ackerman *
PMCID: PMC2822446  NIHMSID: NIHMS169148  PMID: 20129283

Abstract

BACKGROUND

Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

OBJECTIVE

This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.

METHODS

Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.

RESULTS

A total of 2,111 unrelated patients (78% male, mean age 39 ± 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10−53). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14×), F861WfsX90 (11×), D356N (8×), and G1408R (7×). Most mutations localized to the transmembrane-spanning regions.

CONCLUSION

This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.

Keywords: Brugada syndrome, Genetic testing, Ion channels, Sodium channel, Sudden death

Introduction

Brugada syndrome (BrS) is a rare heritable arrhythmia syndrome characterized by an electrocardiographic (ECG) pattern consisting of coved-type ST-segment elevation in the right precordial leads V1 through V3 (often referred to as a type-1 Brugada ECG pattern) and an increased risk for sudden cardiac death (SCD).1,2 The penetrance and expressivity of this autosomal-dominant disorder is highly variable, ranging from a lifelong asymptomatic course to SCD during the first year of life. The syndrome is thought to account for up to 4% of all SCDs and 20% of unexplained sudden death in the setting of a structurally normal heart;3 however, some patients display a more benign course. BrS is generally considered a disorder involving young male adults, with arrhythmogenic manifestation first occurring at an average age of 40 years, with sudden death typically occurring during sleep.4 However, BrS has also been demonstrated in children and infants as young as 2 days old and may serve as a pathogenic basis for some cases of sudden infant death syndrome.3

Since the disorder’s sentinel clinical and ECG description in 1992 by Drs. Pedro and Josep Brugada,5 SCN5A-encoded cardiac sodium channel loss-of-function mutations have been shown to confer the pathogenic basis for an estimated 15% to 30% of BrS, currently representing the most common BrS genotype and classified as Brugada syndrome type 1 (BrS1).6–8 Loss-of-function mutations in SCN5A reduce the overall available sodium current (INa) through either impaired intracellular trafficking of the ion channel to the plasma membrane, thereby reducing membrane surface channel expression, or through altered gating properties of the channel. Gain-of-function SCN5A mutations cause a clinically and mechanistically distinct arrhythmia syndrome, long-QT syndrome type 3 (LQT3). Interestingly, some identical SCN5A mutations may provide either a loss-of-function BrS1-phenotype or a gain-of-function LQT3-phenotype, depending on the individual host. In fact, LQT3/BrS/conduction-disorder SCN5A overlap syndromes do exist within single large families.9,10

After a decade of genetic testing by research laboratories worldwide, BrS genetic testing has made the transition from discovery to translation to clinical implementation with the availability of clinical BrS1 genetic testing (since 2004 in North America and even earlier in Europe), which provides comprehensive open-reading frame and canonical splice site mutational analysis of SCN5A. However, it must be recognized that nearly 2% of healthy Caucasians and 5% of healthy nonwhite subjects also host rare missense SCN5A variants, leading to a potential conundrum in the interpretation of the genetic test results.11 Distinguishing pathogenic mutations from rare harmless genetic variants is of critical importance in the interpretation of genetic testing and the management of genotype-positive BrS patients.

Presently, there are over 100 BrS1-associated mutations publicly available (http://www.fsm.it/cardmoc). We sought to assemble an international compendium of putative BrS1-associated mutations through a retrospective analysis of BrS genomic databases from 9 reference centers throughout the world (5 Europe, 3 United States, 1 Japan) that have each genotyped >100 unrelated cases of clinically suspected BrS. Such a compendium may illuminate further key structure–function properties and provide a foundational building block for the development of algorithms to assist in distinguishing pathogenic mutations from similarly rare but otherwise innocuous ones.

Methods

Study population

A retrospective analysis of BrS databases from 9 centers throughout the world that have each genotyped >100 unrelated cases of clinically suspected BrS was performed. In total, 2,111 unrelated patients (78% male, mean age 39 ± 15 years) were referred for SCN5A genetic testing (Table 1). For the purpose of this compendium of identified mutations, only minimal demographic information for each center’s cohort, such as the average age and range of age at diagnosis and the number of male and female subjects was provided. The specific age and gender were collected for mutation-positive patients. A sample was accepted for genetic testing if the referring physician had made a clinical diagnosis of either possible or definite BrS. An ECG was not always available for each patient. Although DNA samples were accepted for analysis based on a referral diagnosis of BrS, several of the international centers did collect and examine 12-lead ECGs to confirm the presence of an ECG pattern consistent with BrS.

Table 1.

Demographics and mutation yield for 9 Brugada syndrome genetic testing centers

1 2 3 4 5 6 7 8 9
Total 451 365 311 237 195 158 153 130 111
Positive 92 88 69 50 44 26 43 14 12
Age (yrs) 47 ± 14 40 ± 11 45 ± 18 43 ± 14 35 ± 18 36 ± 21 45 ± 15 48 ± 10 37 ± 21
Range (yrs) 3 to 70 0 to 77 0 to 82 8 to 80 0 to 76 0 to 69 5 to 65 28 to 64 7 to 78
 Yield (%) 20.4 24.1 22.2 21.1 22.6 16.5 28.1 10.8 10.8
Male 357 277 239 193 140 117 106 124 72
 Positive 68 67 55 40 31 17 30 13 7
 Yield (%) 21.6 24.2 22.2 20.7 23.4 14.5 28.3 10.5 9.7
Female 94 88 72 44 55 41 47 6 39
 Positive 23 19 14 10 13 9 13 1 5
 Yield (%) 25.5 21.6 19.4 22.7 23.6 22.0 27.7 16.7 12.8
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Center: 1 = Nantes, 2 = Brugada, 3 = AMC, 4 = Paris, 5 = PGxHealth, 6 = MMRL, 7 = UKM, 8 = NCVC, 9 = BCM.

Mutational analysis

Patient genomic DNA was analyzed for mutations in all 27 translated exons, including splice sites and adjacent regions, of the SCN5A-encoded cardiac sodium channel NaV1.5 using a combination of polymerase chain reaction (PCR), either denaturing high-performance liquid chromatography or single-stranded conformation polymorphism and DNA sequencing.12 In addition, frequency, location, and mutation type of SCN5A genetic variation found among 1,300 ostensibly healthy volunteers,11,13 including 649 white subjects and 651 nonwhite subjects (black, Asian, and Hispanic), was analyzed and compared with the possible BrS1-associated mutations. To be reported in this compendium as a possible BrS1-associated mutation, the case mutation must have been absent among all 1,300 control subjects who underwent comprehensive mutation scanning. Further, each reference center examined a local set of control samples from usually 200 to 400 additional unrelated, healthy individuals to determine the presence or absence of each possible case mutation observed in patients from their respective geographical region.

Mutation nomenclature

All possible BrS1-associated mutations were denoted using the accepted Human Genome Variation Society’s guidelines for nomenclature.14 The nucleotide and amino acid designations were based on the SCN5A transcript NM_198056.2. For example, the missense mutation E1784K would indicate the wild-type amino acid (E = glutamic acid) at position 1784 is replaced by lysine (K). Frameshift mutations resulting from nucleotide insertions or deletions were annotated using the F861WfsX90 format, which indicates that the wild-type phenylalanine (F) at position 861 is altered to a tryptophan (W) followed by 89 miscoded amino acids prior to a termination codon (X) 90 residues from the beginning of the altered reading frame.

A substitution of either the first or the last 2 nucleotides of a particular exon has the capacity to alter proper mRNA splicing, regardless of whether the nucleotide substitution codes for a different amino acid (missense mutation) produces a stop codon (nonsense mutation) or does not alter the open reading frame at all (i.e., a synonymous or silent single-nucleotide substitution).15–17 As such, mutations involving this exonic portion of the splice site were considered as possible splicing mutations in this study and annotated as either missense/splicesite, nonsense/splice-site, or silent/splice-site mutations to distinguish them from intronic mutations predicted to disrupt splicing.

Topological placement of the mutations was assigned using a combination of Swissprot (http://ca.expasy.org/uniprot/) and recent studies of the linear topologies for the sodium channel pore-forming alpha subunit.18–20 The Swissprot database provides generally accepted residue ranges corresponding with each ion-channel region and specialized subregions. For Nav1.5, mutations were localized to either the N-terminus (amino acids 1 to 126), interdomain linker (IDL I-II, aa 416-711, IDL II-III, aa 940-1200, and IDL III-IV, aa 1471-1523), transmembrane/linker (Domain I, aa 127-415, Domain II, aa 712-939, Domain III, aa 1201-1470, Domain IV, aa 1524-1772), or C-terminus (aa 1773-2016). The transmembrane-spanning region was further subdivided into S1 through S4 (DI S1-S4/S5, aa 127-252, DII S1-S4/S5, aa 712-841, DIII S1-S4/S5, aa 1201-1336, and DIV S1-S4/S5, aa 1524-1659) and S5 through S6, the pore region and selectivity filter of the channel (DI S5-S6, aa 253-415, DII S5-S6, aa 842-939, DIII S5-S6, aa 1337-1470, DIV S5-S6, aa 1660-1772).

Defining terminology: variant versus mutation

For the purposes of this compendium, a variant will be defined as any change to the wild-type sequence, whether it is in case or control subjects. Mutations will be identified as rare, caseonly (absent in the 1,300+ healthy volunteers) variants that are possibly pathogenic. Variants identified with a minor allele frequency (MAF) >0.5% among the 1,300 healthy control subjects will be termed common polymorphisms. If the MAF is <0.5%, these variants will be termed uncommon/rare polymorphisms.

Defining a variant as a possible BrS1-causative mutation

To be considered as a possible BrS1-causing mutation, the variant must disrupt either the open reading frame (i.e., missense, nonsense, insertion/deletion, or frameshift mutations) or the splice site (polypyrimidine tract, splice acceptor, or splice donor recognition sequences). In addition to the exonic splice sites described above, the acceptor splice site was defined as the 3 intronic nucleotides preceding an exon (designated as IVS−1, −2, or −3) and the donor splice site as the first 5 intronic nucleotides after an exon (designated as IVS+1, +2, +3, +4, or +5).17 Additionally, single-nucleotide substitutions (namely, a purine [A or G] for a pyrimidine [C or T]) within the polypyrimidine tract immediately preceding the acceptor splice-site may be causative.17 As such, some pyrimidine-to-purine substitutions in this region of the intron have been included as potentially pathogenic. For example, an IVS-5 cytosine (C) that falls within the polypyrimidine tract and is substituted by an adenine (A) that would predictably disrupt the polypyrimidine tract and consequently result in aberrant splicing would be included as a possible pathogenic mutation. Hence, single-nucleotide substitutions that obviously did not change the open reading frame (i.e., synonymous single-nucleotide polymorphisms) or those outside of the splice site recognition sequence were not included in either case or control subjects for this study.

Additionally, to be considered as a possible BrS1-causing mutation, the nonsynonymous variant must have been absent in all published databases listing the SCN5A channel common polymorphisms and previously published reports or compendia of rare control variants, e.g., those found in over 2,600 reference alleles (Table 2) derived from over 1,300 ostensibly healthy adult volunteers.11,13 As such, the sole or concomitant presence of a common polymorphism such as H558R-SCN5A or a rarer polymorphism such as A572D-SCN5A would not by definition warrant the annotation of possible BrS1-associated mutation and would not be counted toward the assignment of compound or multiple mutation status to an individual in this compendium. This does not imply that common and rare polymorphisms may not possibly modulate the BrS1 phenotype.

Table 2.

Control variants found in 2,600 reference alleles

Exon Nucleotide change Variant Mutation type Location Number Ethnicity Status
2 52 C>T R18W Missense N-terminal 1 O Rare control
2 100 C>T R34C Missense N-terminal 44 B>H=O>W>A Polymorphism
2 101 G>A R34H Missense N-terminal 1 B Rare control
6 647 C>T S216L Missense DI-S3/S4 4 W Polymorphism
7 856 G>T A286S Missense DI-S5/S6 1 B Rare control
7 872 A>G N291S Missense DI-S5/S6 1 O Rare control
7 895 T>A L299M Missense DI-S5/S6 1 B Rare control
9 1126 C>T R376C Missense DI-S5/S6 1 W Rare control
11 1340 C>G A447G Missense DI/DII 1 B Rare control
11 1345 A>G T449A Missense DI/DII 1 O Rare control
11 1381 T>G L461V Missense DI/DII 2 B Polymorphism
11 1425 A>C R475S Missense DI/DII 1 B Rare control
11 1441 C>T R481W Missense DI/DII 6 B>H=O Polymorphism
12 1571 C>A S524Y Missense DI/DII 18 B>W=H Polymorphism
12 1673 A>G H558R Missense DI/DII 408 W>B>H>O>A Polymorphism
12 1703 G>A R568H Missense DI/DII 1 W Rare control
12 1735 G>A G579R Missense DI/DII 1 W Rare control
12 1776 C>A N592K Missense DI/DII 1 W Rare control
12 1787 A>G D596G Missense DI/DII 1 B Rare control
12 1802 T>C V601A Missense DI/DII 1 W Rare control
12 1852 C>T L618F Missense DI/DII 1 O Rare control
13 1913 G>A G638D Missense DI/DII 1 A Rare control
13 1967 C>T P656L Missense DI/DII 1 B Rare control
13 2014 G>A A672T Missense DI/DII 1 A Rare control
14 2066 G>A R689H Missense DI/DII 1 H Rare control
14 2074 C>A Q692K Missense DI/DII 3 W Polymorphism
14 2114 C>T S705F Missense DI/DII 1 A Rare control
16 2770 G>A V924I Missense DII-S6 2 B=O Polymorphism
17 2924 C>T R975W Missense DII/DIII 1 W Rare control
17 2957 G>A R986Q Missense DII/DIII 1 B Rare control
17 3047 C>T T1016M Missense DII/DIII 1 A Rare control
17 3118 G>A G1040R Missense DII/DIII 1 B Rare control
18 3245 T>C V1082A Missense DII/DIII 1 B Rare control
18 3269 C>T P1090L Missense DII/DIII 5 A>W Polymorphism
18 3292 G>T V1098L Missense DII/DIII 1 A Rare control
18 3308 C>A S1103Y Missense DII/DIII 31 B>O>H Polymorphism
18 3319 G>A E1107K Missense DII/DIII 1 A Rare control
18 3346 C>T R1116W Missense DII/DIII 2 A Polymorphism
20 3578 G>A R1193Q Missense DII/DIII 12 A>W Polymorphism
21 3751 G>A V1251M Missense DIII-S2 1 B Rare control
22 3878 T>C F1293S Missense DIII-S3/S4 2 W Polymorphism
22 3922 C>T L1308F Missense DIII-S4 3 O>B Polymorphism
Intron 24 4299 +2 T>A 1433sp Splice site DIII-S5/S6 1 W Rare control
26 4534 C>T R1512W Missense DIII/DIV 1 H Rare control
28 5360 G>A S1787N Missense C-terminal 3 W Polymorphism
28 5507 T>C I1836T Missense C-terminal 1 B Rare control
28 5701 G>A E1901K Missense C-terminal 1 W Rare control
28 5755 C>T R1919C Missense C-terminal 1 B Rare control
28 5851 G>T V1951L Missense C-terminal 16 H>A>B=O Polymorphism
28 5873 G>A R1958Q Missense C-terminal 1 B Rare control
28 5885 C>T P1962L Missense C-terminal 1 B Rare control
28 5904 C>G I1968M Missense C-terminal 1 B Rare control
28 5972 G>A R1991Q Missense C-terminal 1 B Rare control
28 6010 T>C F2004L Missense C-terminal 7 W>H Polymorphism
28 6016 C>G P2006A Missense C-terminal 3 W>B Polymorphism
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The > and = symbols represent the relative prevalence of the variant of interest in each corresponding ethnicity.

A = Asian; B = black; H = Hispanic; O = other; and W = white.

Results

Overall, 2,111 unrelated patients (78% male, average age at testing 39 ± 15 years) were referred for BrS genetic testing across 9 testing centers (Table 1). As expected, rare SCN5A missense mutations were far more common among BrS cases (438/2,111, 21%) than similarly rare genetic variants were among control subjects (43/1,300 [11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects], P <10−55). The yield differed significantly across centers (P = .0017; chi2 = 24.7, degrees of freedom (df) = 8), ranging from 11% (centers 8 [14/130] and 9 [12/111]) to 28% (center 7 [43/153], P = .0017 for the 9 centers) (Table 1, Figure 1). There was no significant difference in yield between male (324/1,520, 21.3%) and female (112/439, 25.5%, P = .07) subjects. Of the 438 SCN5A mutation-positive cases, 13 (3%) harbored multiple mutations (Table 3). All 13 were male and trended toward younger age at diagnosis (29.7 ± 16.2 years) than male subjects with a single mutation (39.2 ± 14.4 years, P = .07).

Figure 1.

Figure 1

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Mutation detection yield by genetic testing center. Depicted here is a comparison of Brugada syndrome genetic testing for each of the 9 centers ordered according to the total number (N = X) of unrelated patients tested. The number within each column represents the number of genotype positive patients for the respective center. For example, Center 1 analyzed 451 unrelated cases and identified a putative pathogenic mutation in 92 (20%). Center: 1 = Nantes, 2 = Brugada, 3 = AMC, 4 = Paris, 5 = PGxHealth, 6 = MMRL, 7 = UKM, 8 = NCVC, 9 = BCM.

Table 3.

Brugada syndrome patients with multiple SCN5A mutations

Gender Age at
diagnosis
(yrs)		 Mutation 1 Location Mutation 2 Location
M 35 N109K N-terminal V240M DI-S4/S5
M 16 A185V DI-S2/S3 A226V DI-S4
M 44 611+1
 G>A		 DI-S3 V300I DI-S5/S6
M 26 T220I DI-S4 E439K DI-DII
M 21 934+4
 C>T		 DI-S5/S6 G1642E DIV-S4
M 51 P336L DI-S5/S6 I1660V DIV-S5
M 40 L619F DI-DII Q1383X DII-S5/S6
M 49 T632M DI-DII M764R DII-S2
M 2 Q646RfsX5 DI-DII D1243N DIII-S2
M 24 A647D DI-DII P1332L DIII-S4/S5
M 7 G752R DII-S2 K1872N C-terminal
M 41 E1053K DII-DIII R1583C DIV-S2/S3
M 23 R1232W DIII-S1/S2 T1620M DIV-S3/S4
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M = male.

Overall, 293 distinct, possible BrS1-associated mutations (200, 68% novel to this cohort), absent in 2,600 reference alleles, were identified in the 438 genotype-positive cases, 225 (77%) of which were identified only once (Table 4, Figure 2). Only 68 mutations were found in multiple unrelated patients. The 4 most frequent BrS1-associated mutations were E1784K (14 patients), F861WfsX90 (11 patients), D356N (8 patients), and G1408R (7 patients) (Table 4, Figure 2). Two-thirds of the unique mutations were missense mutations (193), whereas the remaining third (100) involved radical mutations (38 frameshift, 32 nonsense, 21 splice-site, and 9 in-frame insertions or deletions) (Table 4, Figure 3).

Table 4.

Compendium of Brugada syndrome-associated SCN5A mutations

Region Nucleotide change Coding effect Mutation type Location No. of unrelated
individuals		 Testing center
Exon 2 3 G>A M1I* Missense N-terminal 1 1
Exon 2 53 G>A R18Q* Missense N-terminal 1 3
Exon 2 191_193delTGC L64del* In-frame del N-terminal 1 5
Exon 2 210 T>G N70K* Missense N-terminal 1 5
Exon 2 217 C>T Q73X* Nonsense N-terminal 1 2
Exon 2 250 G>A D84N* Missense N-terminal 2 1
Exon 3 278 T>C F93S* Missense N-terminal 1 1
Exon 3 281 T>G I94S* Missense N-terminal 1 7
Exon 3 310 C>T R104W* Missense N-terminal 2 1, 2
Exon 3 311 G>A R104Q Missense N-terminal 3 1, 7, 8
Exon 3 327 C>A N109K* Missense N-terminal 1 3
Exon 3 361 C>T R121W* Missense N-terminal 1 8
Exon 3 362 G>A R121Q* Missense N-terminal 2 2, 6
Exon 3 376 A>G K126E Missense N-terminal 1 9
Exon 3 381dupT L128SfsX44* Frame shift DI-S1 1 7
Intron 3 393 −5 C>A* Splice site DI-S1 1 1
Exon 4 407 T>C L136P Missense DI-S1 2 8
Exon 4 410_418dupTCATGTGCA I137_C139dup* In-frame ins DI-S1 1 3
Exon 4 436 G>A V146M* Missense DI-S1 1 7
Exon 4 468 G>A W156X Nonsense DI-S1/S2 1 3
Exon 4 477 T>A Y159X* Nonsense DI-S2 1 5
Exon 4 481 G>C E161Q* Missense DI-S2 1 6
Exon 4 481 G>A E161K Missense DI-S2 3 3, 4
Exon 5 486delC Y162XfsX1* Frame shift DI-S2 1 5
Exon 5 525 G>C K175N* Missense DI-S2 1 1
Exon 5 533 C>G A178G* Missense DI-S2 1 9
Exon 5 535 C>T R179X Nonsense DI-S2/S3 1 2
Exon 5 544 T>C C182R* Missense DI-S2/S3 1 4
Exon 5 554 C>T A185V* Missense DI-S2/S3 1 2
Exon 5 579 G>A W193X* Nonsense DI-S3 1 4
Exon 5 611 C>T A204V* Missense DI-S3 1 4
Intron 5 611 +1 G>A* Splice site DI-S3 1 5
Intron 5 611 +3_611+4dupAA Splice site DI-S3 1 9
Intron 5 612 −2 A>G* Splice site DI-S3 1 4
Exon 6 635 T>A L212Q* Missense DI-S3/S4 1 5
Exon 6 656_657insATTCA T220FfsX10* Frame shift DI-S4 1 2
Exon 6 659 C>T T220I Missense DI-S4 2 2, 3
Exon 6 664 C>T R222X Nonsense DI-S4 4 2, 4
Exon 6 665 G>A R222Q Missense DI-S4 1 4
Exon 6 667 G>C V223L* Missense DI-S4 2 2
Exon 6 673 C>T R225W Missense DI-S4 3 1, 6
Exon 6 677 C>T A226V Missense DI-S4 2 2
Exon 6 694 G>A V232I Missense DI-S4 2 2, 6
Exon 7 718 G>A V240M Missense DI-S4/S5 1 3
Exon 7 745 A>T K249X* Nonsense DI-S4/S5 1 6
Exon 7 808 C>A Q270K* Missense DI-S5 1 6
Exon 7 827 T>A L276Q Missense DI-S5 1 8
Exon 7 832 C>G H278D* Missense DI-S5/S6 1 4
Exon 7 844 C>T R282C* Missense DI-S5/S6 1 2
Exon 7 898 G>A V300I* Missense DI-S5/S6 1 5
Intron 7 934 +1 G>A* Splice site DI-S5/S6 1 3
Intron 7 934 +4 C>T* Splice site DI-S5/S6 1 5
Exon 8 944 T>C L315P* Missense DI-S5/S6 1 6
Exon 8 959 C>A T320N* Missense DI-S5/S6 1 5
Exon 8 974 T>G L325R Missense DI-S5/S6 1 4
Intron 8 998 +1 G>A* Splice site DI-S5/S6 1 4
Exon 9 1007 C>T P336L Missense DI-S5/S6 2 2, 6
Exon 9 1036 G>T E346X Nonsense DI-S5/S6 1 1
Exon 9 1052 G>T G351V Missense DI-S5/S6 1 9
Exon 9 1052 G>A G351D* Missense DI-S5/S6 1 2
Exon 9 1066 G>A D356N Missense DI-S5/S6 8 1, 2, 4, 6, 7
Exon 9 1099 C>T R367C Missense DI-S5/S6 2 3
Exon 9 1100 G>T R367L* Missense DI-S5/S6 1 1
Exon 9 1100 G>A R367H Missense DI-S5/S6 6 1, 2, 8, 9
Exon 9 1106 T>A M369K Missense DI-S5/S6 1 1
Exon 9 1120 T>G W374G* Missense DI-S5/S6 1 1
Exon 9 1127 G>A R376H Missense DI-S5/S6 4 3, 4, 8
Exon 10 1156 G>A G386R* Missense DI-S5/S6 1 1
Exon 10 1157 G>A G386E* Missense DI-S5/S6 2 2
Exon 10 1186 G>C V396L* Missense DI-S6 1 1
Exon 10 1187 T>C V396A* Missense DI-S6 1 2
Exon 10 1255 C>T Q419X* Nonsense DI/DII 1 7
Exon 10 1315 G>A E439K* Missense DI/DII 1 3
Intron 10 1338 +2 T>A* Splice site DI/DII 1 6
Exon 11 1428_1431delCAAG S476RfsX30* Frame shift DI/DII 1 3
Exon 11 1502 A>G D501G Missense DI/DII 1 3
Exon 12 1537delC R513VfsX8* Frame shift DI/DII 1 8
Exon 12 1562delA K521SfsX102* Frame shift DI/DII 1 2
Exon 12 1577 G>A R526H* Missense DI/DII 2 1, 5
Exon 12 1595 T>G F532C Missense DI/DII 1 2
Exon 12 1603 C>T R535X Nonsense DI/DII 4 1, 2, 4, 5
Exon 12 1629 T>A F543L* Missense DI/DII 1 2
Exon 12 1654 G>A G552R* Missense DI/DII 1 9
Exon 12 1717 C>T Q573X* Nonsense DI/DII 1 2
Exon 12 1721delG G574DfsX49* Frame shift DI/DII 1 2
Exon 12 1844 G>A G615E Missense DI/DII 1 4
Exon 12 1855 C>T L619F Missense DI/DII 1 1
Exon 12 1858 C>T R620C* Missense DI/DII 1 1
Exon 12 1890 G>A T630T* Silent/splice site DI/DII 3 1, 3
Intron 12 1890 +5 G>A* Splice site DI/DII 2 2, 5
Exon 13 1895 C>T T632M Missense DI/DII 2 2, 4
Exon 13 1918 C>G P640A* Missense DI/DII 1 3
Exon 13 1936delC Q646RfsX5* Frame shift DI/DII 3 2, 5, 6
Exon 13 1940 C>A A647D* Missense DI/DII 1 5
Exon 13 1943 C>T P648L Missense DI/DII 1 7
Exon 13 1950_1953delAGAT D651AfsX25* Frame shift DI/DII 1 4
Exon 13 1981 C>T R661W* Missense DI/DII 1 5
Exon 13 1983_1993dupGGCCCTCAGCG A665GfsX16* Frame shift DI/DII 1 1
Exon 14 2024_2025delAG E675VfsX45* Frame shift/splice DI/DII 1 2
Exon 14 2047 T>G C683G* Missense DI/DII 1 7
Exon 14 2092 G>T E698X* Nonsense DI/DII 1 2
Exon 14 2102 C>T P701L Missense DI/DII 1 4
Exon 14 2150 C>T P717L* Missense DII-S1 1 6
Exon 14 2201dupT M734IfsX11* Frame shift DII-S1 1 7
Exon 14 2204 C>T A735V Missense DII-S1 4 2, 4, 8, 9
Exon 14 2236 G>A E746K Missense DII-S1/S2 3 1, 2, 7
Exon 14 2254 G>A G752R Missense DII-S2 5 1, 5
Exon 15 2273 G>A G758E* Missense DII-S2 1 2
Exon 15 2274delG I759FfsX6* Frame shift DII-S2 2 5
Exon 15 2291 T>G M764R* Missense DII-S2 1 4
Exon 15 2314 G>A D772N Missense DII-S2/S3 1 1
Exon 15 2317 C>T P773S* Missense DII-S2/S3 1 6
Exon 15 2320delT Y774TfsX28* Frame shift DII-S2/S3 2 3
Exon 15 2326_2328delTAC Y776del* In-frame del DII-S2/S3 1 2
Exon 15 2365 G>A V789I* Missense DII-S3 1 4
Exon 15 2423 G>C R808P* Missense DII-S4 1 1
Exon 15 2435_2436 3delTGGTAinsCGCCT L812P†* Indel/splice site DII-S4 1 5
Exon 16 2465 G>A W822X Nonsense DII-S4 1 4
Exon 16 2516 T>C L839P* Missense DII-S4/S5 1 1
Exon 16 2533delG V845CfsX2* Frame shift DII-S5 1 6
Exon 16 2549_2550insTG F851GfsX19* Frame shift DII-S5 1 2
Exon 16 2550_2551dupGT F851CfsX19* Frame shift DII-S5 1 5
Exon 16 2553 C>A F851L Missense DII-S5 1 2
Exon 16 2582_2583delTT F861WfsX90 Frame shift DII-S5 11 3, 7
Exon 16 2599 G>C E867Q* Missense DII-S5/S6 1 2
Exon 16 2602delC L868X Frame shift DII-S5/S6 2 6, 7
Exon 16 2632 C>T R878C Missense DII-S5/S6 1 2
Exon 16 2633 G>A R878H* Missense DII-S5/S6 5 1, 2, 4, 5, 7
Exon 16 2657 A>C H886P* Missense DII-S5/S6 1 2
Exon 16 2677 C>T R893C* Missense DII-S5/S6 2 4
Exon 16 2678 G>A R893H* Missense DII-S5/S6 3 1, 3, 4
Exon 16 2701 G>A E901K* Missense DII-S5/S6 3 1, 4
Exon 16 2729 C>T S910L Missense DII-S5/S6 1 1
Exon 16 2743 T>C C915R* Missense DII-S6 1 3
Exon 16 2750 T>G L917R* Missense DII-S6 1 2
Exon 16 2780 A>G N927S Missense DII-S6 3 3, 7
Exon 16 2783 T>C L928P* Missense DII-S6 1 1
Exon 17 2804 T>C L935P* Missense DII-S6 1 5
Exon 17 2850delT D951MfsX6* Frame shift DII/DIII 1 4
Exon 17 2893 C>T R965C Missense DII/DIII 3 2, 4, 5
Exon 17 2894 G>A R965H Missense DII/DIII 1 3
Exon 17 2914_2923delTTTGTCAAGC F972GfsX170* Frame shift DII/DIII 1 6
Exon 17 2989 G>A A997T* Missense DII/DIII 1 5
Exon 17 3005_3012delCCAGCTGC P1002HfsX25* Frame shift DII/DIII 1 7
Exon 17 3140_3141dupTG P1048CfsX98* Frame shift DII/DIII 1 3
Exon 17 3157 G>A E1053K Missense DII/DIII 3 1
Exon 17 3164 A>G D1055G* Missense DII/DIII 1 1
Exon 17 3171_3172delTGinsA D1057EfsX88* Insertion/deletion DII/DIII 1 7
Intron 17 3228 +2delT* Splice site DII/DIII 1 3
Exon 18 3236 C>A S1079Y* Missense DII/DIII 1 1
Exon 18 3338 C>T A1113V* Missense DII/DIII 1 5
Exon 18 3345 G>A W1115X* Nonsense DII/DIII 1 6
Exon 19 3419 G>C S1140T* Missense DII/DIII 1 5
Exon 20 3553_3554delCA Q1185GfsX55* Frame shift DII/DIII 1 3
Exon 20 3576 G>A W1192X* Nonsense DII/DIII 1 6
Exon 20 3622 G>T E1208X Nonsense DIII-S1 1 1
Exon 20 3634_3636delATC I1212del* In-frame del DIII-S1 1 2
Exon 20 3656 G>A S1219N Missense DIII-S1 1 1
Exon 20 3666delG A1223PfsX7* Frame shift/splice DIII-S1 1 1
Exon 21 3673 G>A E1225K Missense DIII-S1/S2 4 1, 5, 6, 7
Exon 21 3682 T>C Y1228H Missense DIII-S1/S2 1 1
Exon 21 3694 C>T R1232W Missense DIII-S1/S2 3 1, 2, 9
Exon 21 3695 G>A R1232Q* Missense DIII-S1/S2 1 7
Exon 21 3716 T>C L1239P* Missense DIII-S2 1 2
Exon 21 3727 G>A D1243N* Missense DIII-S2 5 1, 2, 5
Exon 21 3746 T>A V1249D* Missense DIII-S2 1 6
Exon 21 3758 A>G E1253G* Missense DIII-S2 1 1
Exon 21 3784 G>A G1262S Missense DIII-S2 1 1
Exon 21 3813 G>C W1271C* Missense DIII-S3 1 1
Exon 21 3823 G>A D1275N Missense DIII-S3 3 1, 5
Intron 21 3840 +1 G>A Splice site DIII-S3 6 1, 3, 4
Exon 22 3863 C>G A1288G* Missense DIII-S3 1 4
Exon 22 3894delC I1299SfsX13* Frame shift DIII-S4 1 5
Exon 22 3932 T>C L1311P* Missense DIII-S4 1 7
Exon 22 3956 G>T G1319V Missense DIII-S4/S5 5 2, 3, 7
Intron 22 3963 +4 A>G* Splice site DIII-S4/S5 1 5
Intron 22 3963 +2 T>C Splice site DIII-S4/S5 1 1
Exon 23 3968 T>G V1323G* Missense DIII-S4/S5 1 7
Exon 23 3995 C>T P1332L Missense DIII-S4/S5 1 5
Exon 23 4018 G>A V1340I* Missense DIII-S5 1 9
Exon 23 4030 T>C F1344L* Missense DIII-S5 1 1
Exon 23 4036 C>A L1346I* Missense DIII-S5 1 4
Exon 23 4037 T>C L1346P* Missense DIII-S5 1 3
Exon 23 4052 T>G M1351R* Missense DIII-S5 1 2
Exon 23 4057 G>A V1353M* Missense DIII-S5 2 2
Exon 23 4072 G>T G1358W* Missense DIII-S5 1 4
Exon 23 4077 G>T K1359N* Missense DIII-S5 1 4
Exon 23 4079 T>G F1360C Missense DIII-S5/S6 1 1
Exon 23 4088 G>A C1363Y Missense DIII-S5/S6 1 3
Exon 23 4118 T>A L1373X* Nonsense DIII-S5/S6 1 2
Exon 23 4145 G>T S1382I Missense DIII-S5/S6 1 1
Exon 23 4147 C>T Q1383X* Nonsense DIII-S5/S6 1 1
Exon 23 4178 T>A L1393X Nonsense DIII-S5/S6 3 1, 3, 9
Exon 23 4182 C>G Y1394X* Nonsense DIII-S5/S6 1 5
Exon 23 4190delA K1397RfsX2 Frame shift DIII-S5/S6 1 9
Exon 23 4213 G>A V1405M* Missense DIII-S5/S6 2 1, 7
Exon 23 4213 G>C V1405L Missense DIII-S5/S6 2 3
Exon 23 4216 G>C G1406R Missense DIII-S5/S6 1 3
Exon 23 4217 G>A G1406E* Missense DIII-S5/S6 2 5
Exon 23 4222 G>A G1408R Missense DIII-S5/S6 7 1, 4, 5, 7
Exon 23 4226 A>G Y1409C* Missense DIII-S5/S6 1 1
Exon 23 4227 C>G Y1409X* Nonsense DIII-S5/S6 1 8
Exon 23 4234 C>T L1412F* Missense DIII-S5/S6 1 5
Exon 24 4255 A>G K1419E* Missense DIII-S5/S6 1 1
Exon 24 4258 G>C G1420R* Missense DIII-S5/S6 1 3
Exon 24 4279 G>T A1427S* Missense DIII-S5/S6 1 2
Exon 24 4283 C>T A1428V* Missense DIII-S5/S6 1 2
Exon 24 4294 A>G R1432G Missense DIII-S5/S6 1 4
Exon 24 4296 G>C R1432S* Missense DIII-S5/S6 1 2
Exon 24 4298 G>T G1433V* Missense DIII-S5/S6 1 3
Exon 24 4299 G>A G1433G* Silent/splice site DIII-S5/S6 1 4
Intron 24 4299 +1 G>T* Splice site DIII-S5/S6 1 5
Intron 24 4299 +1delG* Splice site DIII-S5/S6 1 1
Intron 24 4300 −1 G>A* Splice site DIII-S5/S6 1 2
Exon 25 4302 T>G Y1434X* Nonsense DIII-S5/S6 1 5
Exon 25 4313 C>T P1438L Missense DIII-S5/S6 1 4
Exon 25 4320 G>A W1440X Nonsense DIII-S5/S6 1 2
Exon 25 4321 G>C E1441Q* Missense DIII-S5/S6 1 7
Exon 25 4342 A>C I1448L* Missense DIII-S6 1 4
Exon 25 4343 T>C I1448T* Missense DIII-S6 1 2
Exon 25 4346 A>G Y1449C* Missense DIII-S6 1 1
Exon 25 4352 T>A V1451D* Missense DIII-S6 1 5
Exon 25 4376_4379delTCTT F1459SfsX3* Frame shift DIII-S6 1 6
Exon 25 4387 A>T N1463Y* Missense DIII-S6 1 2
Exon 25 4389_4396delCCTCTTTA L1464WfsX5* Frame shift DIII-S6 1 8
Exon 25 4402 G>T V1468F* Missense DIII-S6 1 2
Exon 25 4426 C>T Q1476X* Nonsense DIII/DIV 1 4
Intron 25 4437 +5 G>A* Splice site DIII/DIV 2 3, 5
Exon 26 4477_4479delAAG K1493del* In-frame del DIII/DIV 2 1, 7
Exon 26 4477 A>T K1493X* Nonsense DIII/DIV 1 2
Exon 26 4501 C>G L1501V Missense DIII/DIV 1 1
Exon 27 4562 T>A I1521K* Missense DIII/DIV 1 5
Exon 27 4573 G>A V1525M* Missense DIV-S1 1 4
Exon 27 4642 G>A E1548K* Missense DIV-S1/S2 3 1, 4
Exon 27 4708_4710dupATC I1570dup* In-frame ins DIV-S2 1 3
Exon 27 4712 T>G F1571C* Missense DIV-S2 1 4
Exon 27 4720 G>A E1574K Missense DIV-S2 4 2, 6, 7
Exon 27 4745 T>C L1582P* Missense DIV-S2 1 3
Exon 27 4747 C>T R1583C* Missense DIV-S2/S3 2 1, 2
Exon 27 4748 G>A R1583H* Missense DIV-S2/S3 1 1
Exon 27 4773 G>A W1591X* Nonsense DIV-S3 1 2
Exon 27 4810 G>A V1604M* Missense DIV-S3 1 1
Exon 27 4813 +2_4813+5dupTGGG Splice site DIV-S3 1 2
Exon 28 4838 A>T Q1613L* Missense DIV-S3/S4 1 1
Exon 28 4845 C>A Y1615X* Nonsense DIV-S3/S4 1 2
Exon 28 4856delC P1619RfsX12* Frame shift DIV-S3/S4 1 2
Exon 28 4859 C>T T1620M Missense DIV-S3/S4 2 2, 9
Exon 28 4867 C>T R1623X Nonsense DIV-S4 2 2, 3
Exon 28 4868 G>A R1623Q Missense DIV-S4 1 5
Exon 28 4885 C>T R1629X* nonsense DIV-S4 1 3
Exon 28 4886 G>A R1629Q* Missense DIV-S4 1 3
Exon 28 4912 C>T R1638X Nonsense DIV-S4 3 2, 3
Exon 28 4925 G>A G1642E* Missense DIV-S4 1 5
Exon 28 4978 A>G I1660V Missense DIV-S5 5 2, 3, 5, 6
Exon 28 4981 G>A G1661R* Missense DIV-S5 2 1
Exon 28 4981 G>C G1661R* Missense DIV-S5 1 2
Exon 28 4999 G>A V1667I Missense DIV-S5 1 3
Exon 28 5015 C>A S1672Y Missense DIV-S5 2 1, 4
Exon 28 5038 G>A A1680T Missense DIV-S5 2 2, 6
Exon 28 5068_5070delGA D1690HfsX98* Frame shift DIV-S5/S6 1 1
Exon 28 5083 C>T Q1695X Nonsense DIV-S5/S6 2 1, 4
Exon 28 5092 G>A A1698T* Missense DIV-S5/S6 1 2
Exon 28 5124_5126delCAC T1709del* In-frame del DIV-S5/S6 1 4
Exon 28 5126 C>T T1709M Missense DIV-S5/S6 2 1, 8
Exon 28 5126 C>G T1709R* Missense DIV-S5/S6 1 4
Exon 28 5134 G>A G1712S* Missense DIV-S5/S6 1 7
Exon 28 5141 A>G D1714G Missense DIV-S5/S6 1 3
Exon 28 5157delC I1720SfsX67* Frame shift DIV-S5/S6 1 8
Exon 28 5164 A>G N1722D* Missense DIV-S5/S6 1 1
Exon 28 5182 T>C C1728R* Missense DIV-S5/S6 1 2
Exon 28 5184 C>G C1728W* Missense DIV-S5/S6 1 2
Exon 28 5218 G>A G1740R Missense DIV-S5/S6 1 3
Exon 28 5227 G>A G1743R Missense DIV-S5/S6 5 4, 5, 7, 9
Exon 28 5228 G>A G1743E Missense DIV-S5/S6 6 2, 3
Exon 28 5290delG V1764SfsX23* Frame shift DIV-S6 1 8
Exon 28 5290 G>T V1764F Missense DIV-S6 1 7
Exon 28 5336 C>T T1779M Missense C-terminal 1 2
Exon 28 5350 G>A E1784K Missense C-terminal 14 1, 2, 5, 6, 7
Exon 28 5356_5357delCT L1786EfsX2* Frame shift C-terminal 2 1
Exon 28 5387_5388insTGA 1795_1796insD In-frame ins C-terminal 1 3
Exon 28 5420dupA F1808IfsX3* Frame shift C-terminal 1 7
Exon 28 5435 C>A S1812X Nonsense C-terminal 1 7
Exon 28 5464_5467delTCTG E1823HfsX10* Frame shift C-terminal 1 2
Exon 28 5494 C>G Q1832E* Missense C-terminal 1 6
Exon 28 5577_5578dupAA R1860KfsX13* Frame shift C-terminal 1 2
Exon 28 5581 G>A V1861I* Missense C-terminal 1 2
Exon 28 5616 G>C K1872N* Missense C-terminal 1 5
Exon 28 5707 G>C S1904L Missense C-terminal 1 2
Exon 28 5770 G>A A1924T Missense C-terminal 1 3
Exon 28 5803 G>A G1935S Missense C-terminal 1 2
Exon 28 5812 G>A E1938K* Missense C-terminal 1 2
Exon 28 6010_6012dupTTC F2004dup* In-frame ins C-terminal 1 7
Exon 28 6010 T>G F2004V* Missense C-terminal 1 5
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del = deletion; dup = duplication; ins = insertion; indel = insertion/deletion; ins = insertion

*

novel mutation

Testing Center: 1 = Nantes; 2 = Brugada; 3 = AMC; 4 = Paris; 5 = PGxHealth; 6 = MMRL; 7 = UKM; 8 = NCVC; 9 = BCM.

Figure 2.

Figure 2

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BrS1-associated mutation frequency distribution. This bar graph summarizes the distribution of specific mutations among unrelated patients. The Y-axis depicts the number of unique BrS1-associated mutations, and the X-axis represents the number of unrelated patients. For example, the first column indicates that there were 226 unique mutations each observed only once. The last column indicates that 4 different BrS1-associated mutations were each seen in ≥7 unrelated patients. The inset shows the 4 most common BrS1-associated mutations identified and the number of specified unrelated patients in whom the mutations were found.

Figure 3.

Figure 3

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Summary of SCN5A mutation type for BrS1. The distribution of mutation type (missense, frameshift, etc.) is summarized for the possible BrS1-associated SCN5A mutations. The number within the column represents the total number of unique mutations for the respective type. For example, there were 193 unique missense mutations identified.

Of the 293 unique mutations, 208 (71%) localized to one of the 4 transmembrane-spanning regions (DI, DII, DIII, or DIV), 54 (18%) localized to an IDL (31 in IDL I-II, 17 in IDL II-III, and 6 in IDL III-IV), 17 (6%) localized to the C-terminus, and 14 (5%) localized to the N-terminus (Table 4, Figure 4). The majority of patients with a single SCN5A mutation (313/425, 74%) hosted a mutation that localized to the transmembrane region of the channel, with 31% (133/425) having a mutation that localized to either DI S1-S4, DII S1-S4, DIII S1-S4, or DIV S1-S4 and 42% (180/425) having a mutation that localized to the S5, P-loop, and S6 regions containing the pore and selectivity filter of the sodium channel (DI S5-S6, DII S5-S6, DIII S5-S6, or DIV S5-S6) (Table 4, Figure 4). In fact, compared with the topological location for the rare control variants, there was a strong predilection for a patient’s possible BrS1-associated mutation to localize to the channel’s transmembrane (S1-S4 6.3% vs. 0.2%, P <10−24) and pore-forming segments (S5-S6 8.5% vs. 0.5%, P <10−30) (Figure 5). Twenty-eight patients (1.3%) had their possible BrS1-associated missense mutation localizing to the DI-DII or DII-DIII linker domains, where the vast majority of the rare missense SCN5A variants, which were discovered among the ostensibly healthy control subjects, reside. The yield for the linker regions was 3% for cases compared with 1.7% for healthy subjects (P = NS) (Figure 5).

Figure 4.

Figure 4

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Channel topology of NaV1.5’s pore-forming alpha subunit encoded by SCN5A and location of putative BrS1-causing mutations. Missense mutations are indicated by white circles, whereas mutations other than missense (i.e., frameshift, deletions, splice-site, etc.) are depicted as gray circles. In addition, 4 different circle sizes are used, with the smallest circle indicating a mutation seen only once; a medium-sized circle for mutations observed in 2, 3, or 4 unrelated patients; a large circle for mutations observed in 5, 6, 7, 8, or 9 patients; and the largest circle indicating those mutations observed in at least 10 unrelated patients.

Figure 5.

Figure 5

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Yield of missense mutations/rare variants in cases and control subjects by location. A comparison of the yield of rare, missense case mutations/control variants in 2,111 cases versus 1,300 control subjects by protein location. * = p<0.05.

Interestingly, 10 (3.4%) of the mutations, identified in 29 patients of this BrS compendium, have been identified previously in cases of long-QT syndrome (LQTS): G615E, L619F, E1225K, P1332L, L1501V, R1623Q, I1660V, V1667I, T1779M, including the most common BrS1-associated mutation, E1784K, observed in this BrS compendium. Five of the 10 have been functionally characterized previously, with L619F,21 P1332L,22 R1623Q,23 and E1784K24 producing channel abnormalities consistent with an LQT3 phenotype and G615E25 producing a wild-type-like SCN5A channel.10

Discussion

Since the first report by Chen et al26 in 1998, a little over 100 unique SCN5A mutations have been implicated as possibly causative for BrS1. Previous small cohort studies have indicated that the prevalence of SCN5A mutations in BrS is roughly 15% to 20%, and possibly as high as 40% in cases of familial BrS. In 2000, Priori et al6 reported a 15% yield with respect to SCN5A mutations among 52 unrelated patients. In 2002, these investigators extended their analysis to 130 probands (20% with a family history of sudden unexplained death) and identified an SCN5A mutation in 22%.7 Schulze-Bahr et al8 reported a 14% yield among 44 unrelated BrS patients, who are included in the current compendium.

Here, through this international multicenter study, we provide an expanded compendium of 293 unique (200 novel) BrS1-associated SCN5A mutations derived from over 2,100 unrelated patients referred for BrS genetic testing. The overall yield was 21% and ranged from 11% to 28% among the 9 centers. The differences in yield between the centers may be due to technical differences in mutational analysis methods used among laboratories, but it more likely reflects phenotypic differences among cohorts. For example, the cohorts with the lowest yield may have a preponderance of sporadic cases compared with familial cases. In 2003, Schulze-Bahr et al8 reported that although none of their 27 sporadic BrS cases hosted an SCN5A mutation, 38% of their index cases with clearly familial BrS were positive. The number of sporadic versus familial BrS patients for each center’s cohort is currently unknown. Alternatively, some of the lower yield centers may have accepted a greater proportion of weaker clinical cases for BrS genetic testing because no particular litmus test was demanded before acceptance of a sample.

Eight of the 9 centers represent research-based genetic testing laboratories, where most often the cohorts for such laboratories are composed of phenotypically robust cases of BrS. However, 1 center (center 5 in Table 1) represents a clinical laboratory offering the commercially available, fee-based genetic test for both BrS1 and LQTS. In this setting, the level of clinical suspicion and the usage of the genetic test by the referring physician are unknown for each patient sample submitted. Among their first 195 BrS referral cases submitted for clinical genetic testing, 22.6% were identified with a possible pathogenic SCN5A mutation, which is in line with the higher point estimate of a 20% prevalence of SCN5A mutations among clinically strong cases of BrS patients,7 and consistent with the noncommercial centers in this compendium. In contrast, this laboratory has reported a yield of 36% for the first 2,500 consecutive unrelated LQTS referral cases tested compared with a yield of 75% among clinically strong cases of LQTS.27 These observations suggest that in clinical practice, prescribing cardiologists are submitting higher-probability BrS cases for BrS1 genetic testing compared with LQTS.

In this compendium, 3% of the genotype-positive patients hosted multiple putative pathogenic SCN5A mutations, absent in control subjects. Akin to genotype–phenotype observations in LQTS,28 patients hosting multiple SCN5A mutations were younger at diagnosis (29.7 ± 16 years) than those having a single mutation. Nearly half of the 13 cases (all male) with multiple mutations were younger than 25 years of age, with the youngest presenting at 2 years of age. Whether carriers of multiple mutations had a more severely expressed phenotype, such as having more multiple syncopal events, aborted cardiac arrest, or stronger family history of SCD, than single-mutation carriers is unknown.

Mutations in this compendium overwhelmingly represent “private” mutations, meaning they were seen only once. Nearly 80% of the 293 unique mutations were identified in a single unrelated case. Fewer than 20 mutations were seen in more than 3 unrelated BrS patients. However, nearly 10% of the 438 unrelated SCN5A mutation-positive patients hosted 1 of 4 mutations: E1784K (14 patients), F861WfsX90 (11 patients), D356N (8 patients), and G1408R (7 patients). In this compendium, more than one-third of the genotype-positive patients had radical or non-missense mutations (i.e., frameshift, nonsense, and splicing errors) that represent extremely high-probability case mutations (only 1 such variant was found in 1 of the 1,300 healthy volunteers) and would predictably cause a significant loss of sodium channel function through a mechanism of haploinsufficiency. Recently, Meregalli et al29 reported that BrS patients with truncation mutations, caused by radical mutations, had a more severe phenotype characterized as a higher propensity for syncope and prevalence of SCD among young first-degree relatives, than those BrS patients hosting missense mutations functionally characterized with ≤90% peak sodium current reduction.

The SCN5A-encoded cardiac voltage-gated sodium channel (Nav1.5), which is responsible for the initial fast upstroke of the cardiac action potential and accordingly plays a vital role in the excitability of myocardial cells and the proper conduction of the electrical pulsation of the heart, consists of 4 homologous domains (DI-DIV) that are connected by intracellular linkers. Each domain contains 6 transmembrane-spanning segments (S1-S6). Although case mutations were scattered throughout Nav1.5, there was clustering of putative BrS1-associated mutations whereby nearly three-fourths localized to the transmembrane and pore-forming domains compared with <20% of the rare variants found among the control subjects. Further, nearly 10% of patients with clinically suspected BrS had a mutation localizing to the channel’s pore/selectivity filter (segments S5 and S6 and the interconnecting P-loops) compared with <0.5% of the control subjects. Because of the extreme rarity of pore-localizing missense variants among the healthy control subjects, such missense mutations found in cases are high probability BrS1-causative mutations. However, whether BrS1 patients with pore mutations behaved more poorly than those with mutations localizing to other domains was unable to be gleaned in this study.

In contrast, only 25 patients hosted a single missense mutation residing in either the DI-DII or DII-DIII linker domains. The observed preponderance (over 50% of which localize to these 2 IDLs) of the 42 unique rare missense variants identified in the healthy control subjects suggest that some of the 21 IDL localizing, possible BrS1-associated missense mutations that were identified in 25 cases may in fact represent false positives.11,13 Despite being absent in over 1,300 control subjects, either cosegregation or functional studies on these DI-DII and DII-DIII linker-localizing mutations should be considered before upgrading their status from a rare variant of uncertain significance to a probable BrS1-causative missense mutation. For example, 1 of the 21 missense mutations, G615E, has been previously characterized as having no significant changes in current density or kinetics compared with wild type, casting some doubt on its level of causality.25

Whereas loss-of-function mutations in SCN5A have been shown to serve as a pathogenic basis for BrS, gain-of-function mutations in SCN5A provide the pathogenic substrate for LQT3, a clinically and mechanistically distinct arrhythmia syndrome from BrS. Interestingly, 10 mutations identified in this BrS compendium have been implicated previously in LQTS, including the most commonly observed mutation, E1784K. In fact, E1784K represented the most commonly observed SCN5A mutation (4/26, ~15%) among a cohort of 541 unrelated LQTS patients.28 Although the clinical phenotype for the patients hosting 1 of these 10 mutations could have been assigned incorrectly, it is far more likely that these represent overlap syndrome/mixed phenotype syndrome–associated SCN5A mutations.

For example, E1784K represents the quintessential example of a cardiac sodium channel mutation with the capacity to provide for a mixed clinical phenotype of LQT3, BrS, and conduction disorders.30 Makita et al30 reported recently a high prevalence of LQT3/BrS/conduction phenotype overlap among 41 E1784K carriers from 15 kindreds of diverse ethnic background. Of the 41 cases, 93% displayed a prolonged QTc, 22% with a diagnostic indicator (ST-segment elevation or positive provocation test) of BrS, and 39% had sinus node dysfunction. Functional characterization of mutant E1784K sodium channels displayed unique biophysical and pharmacological properties consistent with other mutations that yield a mixed phenotype, including a negative shift of steady-state sodium channel activation and enhanced tonic block in response to sodium channel blockers, leading to an additional BrS/sinus node dysfunction phenotype in conjunction with a prolonged QTc.30 This particular functional effect may influence the pharmacological management of patients with E1784K-SCN5A disease.30

Similarly, Bezzina et al31 in 1999, described an LQT3/BrS overlap phenotype in a large 1795insD-SCN5A mutation–positive 8-generation kindred characterized with a high incidence of sudden nocturnal death, QT-interval prolongation, and Brugada ECG. Whether or not the 9 other mutations, identified here in BrS patients and elsewhere in patients purported to have LQTS, have a similar functional characteristic that provides a substrate for producing a mixed/overlapping clinical phenotype remains to be seen.

Given that SCN5A remains the most common BrS genotype despite accounting for only 20% of BrS, genetic heterogeneity of the disease is evident and the role of genetic background in the pathophysiology of BrS is important.32 Recently, mutations in the glycerol-3-phosphate dehydrogenase 1–like protein encoded by GPD1L have been shown to affect trafficking of the sodium channel to the plasma membrane, thus reducing overall sodium current, giving rise to the BrS phenotype.33 Recently, mutations involving the L-type calcium channel alpha and beta subunits encoded by the CACNA1C and CACNB2b genes, respectively, were implicated in nearly 11% of BrS cases.34 Other minor causes of BrS include mutations in the sodium channel beta 1 subunit encoded by SCN1B and in a putative beta subunit of the transient outward potassium channel (Ito) encoded by KCNE3.35,36 The most recent gene associated with BrS is the SCN3B-encoded beta-3 subunit of the cardiac sodium channel.37

A number of these minor BrS-susceptibility genes function in part as sodium channel interacting proteins (ChIPs). The cardiac sodium channel is now understood to be a part of a macromolecular complex, with numerous ChIPs regulating its expression, localization, and function. As exemplified by GPD1L, SCN1B, and SCN3B, other genes, which encode other sodium ChIPs whose disruption would portend a loss of function sodium channel phenotype, would warrant examination as candidate BrS disease or disease-modifying genes. These 6 minor BrS-susceptibility genes (GPD1L, CACNA1C, CACNB2B, SCN1B, SCN3B, and KCNE3) have not been examined among the remaining 1,673 SCN5A-negative unrelated cases represented in this compendium, but it is predicted that these minor genes will explain <10% of this cohort. Thus, the majority of BrS still remains genetically elusive.

Study limitations

For the purpose of this compendium of identified mutations, only minimal demographic information from each center’s cohort was made available because the focus was on the prevalence, spectrum, and localization of SCN5A mutations among suspected cases of BrS rather than an attempt to establish any particular genotype–phenotype correlates. Nevertheless, there is significant clinical value due to the data in aggregate. For example, the rare missense mutations seen numerous times among these cases referred for BrS genetic testing, and still not among the control subjects, indicate high-probability BrS-associated mutations.

Furthermore, despite the lack of clinical information, the physical distribution of mutations/variants among cases and control subjects is very telling, whereby the power in numbers can come from the series of mutations/variants clustering in a region, even if the individual mutations/variants have only been observed rarely. For example, even without cosegregation data or in vitro function analyses, the next rare, nonmissense mutation as well as the next transmembrane-localizing missense mutation represent high-probability pathogenic substrates. Conversely, those rare single amino acid substitutions localizing to the domain I-II and II-III linkers should be buttressed with either clinical cosegregation data or in vitro functional data before being upgraded from this list of possible deleterious mutations to highly probable deleterious mutations.

Additionally, this analysis focused on only identifying coding and splicing region single-nucleotide mutations and small insertion/deletion mutations by molecular techniques that often do not detect larger rearrangements, insertions, and deletions. SCN5A promoter region mutations, deep intronic mutations, epigenetic methylation mutations, and large genomic rearrangements, all of which could predictably produce a loss-of-function phenotype, would have escaped detection by the mutational analyses performed herein. However, such alterations are quite uncommon when compared with changes in the known coding sequences of the genes.

Despite these limitations, this compendium of nearly 300 distinct BrS-associated mutations provides key observations that may assist in the further interrogation of the cardiac sodium channel biology and serve as a foundation for the development of algorithms to assist in distinguishing pathogenic mutations from similarly rare but otherwise innocuous ones.

Conclusion

Since the sentinel discovery of BrS as a cardiac channelopathy in 1998, our genomic understanding of this potentially lethal disorder has matured from a phase of discovery to one of translational medicine. This international consortium of BrS genetic testing centers has tripled the catalog of possible BrS1-associated mutations with the addition of 200 new mutations to the public domain and has provided a template to draw upon for further genetic testing interpretation and biological inquiry.

Acknowledgments

Support for data analysis for this project was provided by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (Dr. Ackerman), grant HL47678 from the National Institutes of Health (Dr. Antzelevitch), New York State and Florida Free and Accepted Masons, the GIS Institut des Maladies Rares, the AFM (ANR-06-MRAR-022, PG, Dr. Schott), The Health Sciences Research Grants (H18, Research on Human Genome, 002) and the Research Grant for the Cardiovascular Diseases (21C-8) from the Ministry of Health, Labor, and Welfare of Japan (Dr. Shimizu), The Fondation Leducq Trans-Atlantic Network of Excellence Grant (05 CVD 01, Preventing Sudden Death, Dr. Schott), ANR grant ANR/-05-MRAR-028-01 (Dr. Schott), grant from the Fondation pour la recherche Medicale (Dr. Schott), FIS-ISCiii (Dr. Brugada), CNIC (Dr. Brugada), Ramon Brugada Sr. Foundation (Dr. Brugada), Leducq Foundation, grant 05 CVD, Alliance against Sudden Cardiac death (Drs. Wilde, Schott, and Schulze-Bahr), and Deutsche For-schungsgemeinschaft (Dr. Schulze-Bahr). All mutational analyses performed in this study were conducted at individual centers. Dr. Ackerman is a consultant for PGxHealth. Intellectual property derived from Dr. Ackerman’s research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals).

ABBREVIATIONS

BrS

Brugada syndrome

BrS1

Brugada syndrome type 1

ChIPs

sodium channel interacting proteins

ECG

electrocardiographic

IDL

interdomain linker

INa

available sodium current

LQT3

long-QT syndrome type 3

LQTS

long-QT syndrome

MAF

minor allele frequency

PCR

polymerase chain reaction

SCD

sudden cardiac death

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