Table 3.

Mutations associated with the BrS.

Gene	Protein	Current	Effect	Function	Prevalence
GENES ENCODING ION CHANNEL SUBUNITS
1. Major BrS-susceptibility genes
SCN5A	NaV1.5 (α-subunit of the voltage-dependent Na+ channel)	↓ INa	loss-of-function	mediator of the depolarizing inward sodium INa current	⋍25% (BrS1)
2. Rare BrS-susceptibility genes
By decreasing inward currents
SCN1B	β1-subunit of the voltage-dependent Na+ channel	↓ INa	loss-of-function	auxiliary protein modulator of NaV1.5 and the INa current	<1%
SCN2B	β2-subunit of the voltage-dependent Na+ channel	↓ INa	loss-of-function	auxiliary protein modulator of NaV1.5 and the INa current	<1%
SCN3B	β3-subunit of the voltage-dependent Na+ channel	↓ INa	loss-of-function	auxiliary protein modulator of NaV1.5 and the INa current	<1%
SCN10A	NaV1.8 (α-subunit of the neuronal voltage-dependent Na+ channel)	↓ INa	loss-of-function	mediator of the depolarizing phase of the neural AP, associated with pain perception	⋍10%?
CACNA1C	CaV1.2 (α1C-subunit of the volatge-dependent L-type Ca2+ channel)	↓ ICaL	loss-of-function, combined phenotype of BrS and SQTS	mediator of the inward calcium ICaL current	<1%
CACNB2b	β2-subunit of the voltage-dependent L-type Ca2+ channel	↓ ICaL	loss-of-function, combined phenotype of BrS and SQTS	auxiliary protein modulator of CaV1.2 and the ICaL current	<1%
By increasing outward currents
KCND3	KV4.3 (α-subunit of the voltage-dependent K+ channel)	↑ Ito	gain-of-function	mediator of the transient outward K+ Ito current	<1%
KCNE3	minK-related peptide 2 (β-subunit of the voltage-dependent K+ channel)	↑ Ito	gain-of-function	regulator of KV4.3	<1%
KCNAB2	β2-subunit of the voltage-dependent K+ channel	↑ Ito	gain-of-function	interaction with KV4.3	<1%
KCND2	KV4.2 (voltage-dependent K+ channel)	↑ Ito	gain-of-function	contributor to the transient outward K+ Ito current	<1%
KCNE5	minK-related peptide 4 (β-subunit of the voltage-dependent K+ channel)	↑ Ito	gain-of-function	inhibitor of the delayed rectifying KV7.1 channel and modulator of KV4.3	<1%
KCNJ8	Kir6.1 (inward-rectifier K+ channel, subunit of the ATP-sensitive K+ channel)	↑ IK-ATP	gain-of-function	mediator of the IK-ATP currents	<1%
ABCC9	SUR2 (sulfonylurea receptor, subunit of the ATP-sensitive K+ channel)	↑ IK-ATP	gain-of-function	modulator of IK-ATP currents	<1%
KCNH2	KV11.1/hERG (α-subunit of the voltage-dependent K+ channel)	↑ IKr	gain-of-function	mediator of the rapid component of the delayed rectifying potassium IKr current	<1%
Less established mechanisms
CACNA2D1	α2/δ subunit of the volatge-dependent L-type Ca2+ channel	↓ ICaL?	loss-of-function?, combined phenotype of SQTS and BrS	auxiliary protein modulator of CaV1.2 and the ICaL current	<1%
HCN4	hyperpolarization-activated, cyclic nucleotide-gated ion channel 4	↓ If?	loss-of-function?	mediator of the pacemaker current, If	<1%
TRPM4	Transient receptor potential melastatin 4		loss-of-function/gain-of-function	regulator of conduction and cellular electrical activity which impact heart development	<1%
GENES ENCONDING AUXILIARY PROTEINS
FGF12	fibroblast growth factor 12	↓ INa	interaction with NaV1.5 trafficking	modulator of Nav1.5 and the INa current	<1%
GPD1L	glycerol-3-phosphate dehydrogenase 1-like	↓ INa	interaction with NaV1.5 trafficking	modulator of Na1.5 and the INa current	<1%
SLMAP	sarcolemma associated protein (striatin-interacting phosphatase and kinase complex)	↓ INa	interaction with NaV1.5 trafficking	present in the T-tubules, regulator of excitation-contraction coupling	<1%
PKP2	plakophillin-2	↓ INa	changes in NaV1.5 expression in intercalated disc	binds to and modulates NaV1.5 and the INa current	<1%
SEMA3A	semaphorin-3A	↑ Ito	loss-of-function	inhibitor of the KV4.3 channel	<1%
Less established mechanisms
RANGRF	MOG1 (multicopy suppressor of Gsp1)	↓ INa?	interaction with NaV1.5 trafficking	involved in nuclear protein import—regulates cell surface location of NaV1.5	<1%
HEY2	CHF1 (cardiovascular helix-loop-helix factor 1)	↑ Ito?	interaction with KCNIP2	transcriptional regulator of cardiac electrical function	<1%

↑: increased current; ↓: decreased current; ?: suspected but not confirmed mechanism.