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Multicenter Study
. 2015 Jun 1;106(3):520-9.
doi: 10.1093/cvr/cvv042. Epub 2015 Feb 17.

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Elijah R Behr  1 , Eleonora Savio-Galimberti  2 , Julien Barc  3 , Anders G Holst  4 , Evmorfia Petropoulou  5 , Bram P Prins  5 , Javad Jabbari  6 , Margherita Torchio  7 , Myriam Berthet  8 , Yuka Mizusawa  3 , Tao Yang  2 , Eline A Nannenberg  9 , Federica Dagradi  7 , Peter Weeke  2 , Rachel Bastiaenan  5 , Michael J Ackerman  10 , Stig Haunso  11 , Antoine Leenhardt  12 , Stefan Kääb  13 , Vincent Probst  14 , Richard Redon  14 , Sanjay Sharma  5 , Arthur Wilde  15 , Jacob Tfelt-Hansen  11 , Peter Schwartz  7 , Dan M Roden  2 , Connie R Bezzina  3 , Morten Olesen  16 , Dawood Darbar  2 , Pascale Guicheney  8 , Lia Crotti  17 ; UK10K Consortium; Yalda Jamshidi  1
Affiliations
Multicenter Study

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Elijah R Behr et al. Cardiovasc Res. .

Erratum in

Abstract

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.

Methods and results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970).

Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

Keywords: Brugada syndrome; Genetics; QRS duration; Rare variants; SCN10A.

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Figures

Figure 1
Figure 1
Representation of Nav1.8 channel protein and the corresponding localization of 12 rare variants of which six were novel (E19K, A200V, I671V, G590R, R1121C, G1299A) and the common BrS associated SNP (V1073).
Figure 2
Figure 2
Pedigree 1 demonstrates the cis inheritance of SCN10A I671V and G1299A in father (I:1) and son (II:1). The ECGs shows a spontaneous type 1 ECG pattern in lead V1 in (I:1) and an ajmaline-induced type 1 pattern in leads V1 and V2. Pedigree 2 shows the failure of the A200V mutation to segregate with phenotype. The ECGs demonstrate the type 1 pattern in all three individuals in the 3rd intercostal space after ajmaline provocation. SCD, sudden cardiac death; V1-3, V2-3, and V3-3 are leads V1–V3 displaced to the 3rd intercostal space.
Figure 3
Figure 3
Representative traces obtained for the SCN10A common variants A1073 and V1073, and rare variants A200V and I671V transiently expressed in ND7/23 cells (n = 5 cells/group). Inset in (A) represents the voltage-clamp protocol.
Figure 4
Figure 4
(A–C) Current–voltage relationships obtained for SCN10A common variants A1073 and V1073, and rare variants A200V and I671V expressed in ND7/23 cells (n = 6–9 cells/group). Inset in (A) shows the representation of the voltage-clamp protocol used. (D–F) Voltage-dependence of activation and inactivation for studied variants expressed in ND7/23 cells. The data are presented as peak currents normalized by the peak INa obtained at test potential = +10 mV. The average data for the A1073 common variant is presented in each panel for comparison. Data are expressed as mean ± SE.
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Comment in

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