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

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 (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). 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.

Figures

Figure 1

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.

Figure 2

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

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.

Figure 4

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

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