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Supplementary Table 1 Molecular and Genetic Characteristics of Inherited Cardiac Channelopathies

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Supplementary Table 1 Molecular and Genetic Characteristics of Inherited Cardiac Channelopathies Supplementary Table 1 Molecular and genetic characteristics of inherited cardiac channelopathies Disorder Affected Subtype Inheritance Locus Gene Protein Functional Effect of Frequency in Evidence on PMID Ion Current/ Mutation phenotype (%) pathogenicity Protein LQTS Potassium LQTS1 AD (RWS) 11p15.5-p15.4 KCNQ1 Kv7.1 (potassium voltage-gated loss-of-function, reduced IKs 30-35% (RWS) C, F, S 8528244 AR (JLNS) channel subfamily Q member 1) ~90.5% (JLN) LQTS2 AD (RWS) 7q36.1 KCNH2 Kv11.1 (HERG, potassium voltage- loss-of-function, reduced IKr 25-30% (RWS) C, F, S 7889573 gated channel subfamily H member 2) LQTS5 AD (RWS) 21q22.12 KCNE1 MinK (potassium voltage-gated loss-of-function, reduced IKs <1% (RWS) C, F, S 9354802, AR (JLNS) channel subfamily E regulatory <0.5% (JLN) 9354783 subunit 1) LQTS6 AD (RWS) 21q22.11 KCNE2 MiRP1 (potassium voltage-gated loss-of-function, reduced IKr <1% (RWS) C, F; S 10219239 channel subfamily E regulatory subunit 2) LQTS13 AD (RWS) 11q24.3 KCNJ5 Kir3.4 (potassium voltage-gated loss-of-function, reduced rare C, F, S 24574546 channel subfamily J member 5) IKACh LQTS7 AD (ATS) 17q24.3 KCNJ2 Kir2.1 (potassium voltage-gated loss-of-function, reduced IK1 <1% (RWS) C, F, S 11371347 channel subfamily J member 2) Potassium- LQTS11 AD (RWS) 7q21.2 AKAP9 Yotiao (A-kinase anchoring protein loss-of-function, reduced IKs C, F 18093912 associated 9) Sodium LQTS3 AD (RWS) 3p22.2 SCN5A Nav1.5 (sodium voltage-gated gain-of-function, increased 5-10% (RWS) C, F, S 7889574, channel alpha subunit 5) late INa inward current 7651517, 11136691 LQTS10 AD (RWS) 11q23.3 SCN4B Navb4 (sodium voltage-gated channel gain-of-function, increased rare C, F, S 17592081 beta subunit 4) late INa inward current Sodium- LQTS9 AD (RWS) 3p25.3 CAV3 caveolin 3 increased late INa inward <1 (RWS) C, F, S 17060380 associated current LQTS12 AD (RWS) 20q11.21 SNTA1 syntrophin alpha 1 (a-syntrophin) increased late INa inward rare C, F 18591664 current Calcium LQTS8/TS AD (RWS/TS) 12p13.3 CACNA1C Cav1.2 (calcium voltage-gated gain-of-function, increased rare C, F, S 15454078, channel subunit alpha1 C) ICaL 15863612, 23677916 - AD (RWS) 1q43 RyR2 ryanodine receptor 2 uncontrolled calcium release rare C from the SR Calcium- LQTS14 AD 14q32.11 CALM1 calmodulin 1 impaired calcium-dependent rare C, F, S 23388215, associated inactivation of the L-type Ca 26969752 channels, or increased late INa inward current LQTS15 AD 2p21 CALM2 calmodulin 2 impaired calcium-dependent rare C, F 23388215, inactivation of the L-type Ca 26969752, channels 24917665 LQTS16 Unknown 19q13.32 CALM3 calmodulin 3 impaired calcium-dependent rare C 26969752, inactivation of the L-type Ca 25460178 channels (?) - AR 6q22.31 TRDN triadin (part of calcium release slower calcium-dependent rare C, S 25922419 complex) inactivation of the L-type Ca channels Multiple ion LQTS4/ABS AD 4q25-q26 ANK2 ankirin-2 (ankyrin B) loss-of-function, instability rare C, F, S 12571597, currents (RWS/ABS) of Na/Ca exchanger 15178757 CPVT Calcium CPVT1 AD 1q42.1-q43 RyR2 ryanodine receptor 2 uncontrolled calcium release 55-60% C, F, S 11208676 from the SR CPVT2 AR 1p13.1 CASQ2 calsequestrin 2 uncontrolled calcium release 1-2% C, F, S 11704930 from the SR Calcium- CPVT4 AD 14q32.11 CALM1 calmodulin 1 loss-of-function, rare C, F, S 23040497 associated spontaneous Ca wave and spark activity CPVT5 AR 6q22.31 TRDN triadin (part of calcium release loss-of-function, slower rare C, F, S 22422768 complex) calcium-dependent inactivation of the L-type Ca channels CPVT with Calcium - AD 2p21 CALM2 calmodulin 2 loss-of-function, rare C, F 24917665 prolonged associated spontaneous Ca wave and QT interval spark activity - Unknown 19q13.32 CALM3 calmodulin 3 loss-of-function, rare C, F 27516456 spontaneous Ca wave and spark activity CPVT3 AR 4q13 TECRL trans-2,3-enoyl-CoA reductase-like elevated diastolic [Ca2+]I, rare C, F, S 17666061, decreased SERCA and 27861123 Na/Ca exchanger activities BrS Sodium BrS1 AD 3p22.2 SCN5A Nav1.5 (sodium voltage-gated loss-of-function, reduced INa 20-25% C, F, S 9521325, channel alpha subunit 5) (Caucasian) 20129283 10-15% (Asian) BrS5 AD 19q13.11 SCN1B Navb1 (sodium voltage-gated channel loss-of-function, reduced INa 1-2% C, F, S 22155597, beta subunit 1) & increased transient 18464934 outward potassium current Kv4.3 BrS17 AD 11q23.3 SCN2B Navb2 (sodium voltage-gated channel loss-of-function, reduced rare C, F 23559163 beta subunit 2) expression of Nav1.5 and reduced INa BrS7 AD 11q24.1 SCN3B Navb3 (sodium voltage-gated channel loss-of-function, reduced rare C, F 20031595 beta subunit 3) expression of Nav1.5 and reduced INa BrS18 AD 3p22.2 SCN10A Nav1.8 (sodium voltage-gated loss-of-function, reduced INa <2% C, F, S 24998131, channel alpha subunit 10, modulate 25842276 the activity of Nav1.5) Sodium- BrS11 AD 17p13.1 RANGRF MOG1 (RAN guanine nucleotide loss-of-function, reduced rare C, F 21447824 associated (MOG1) release factor, regulates the surface expression of Nav1.5 and expression of Nav1.5) reduced INa BrS2 AD 3p22.3 GPD1L glycerol-3-phosphate dehydrogenase loss-of-function, reduced <2% C, F, S 17967977 1-like expression of Nav1.5 and reduced INa BrS15 AD 3p14.3 SLMAP sarcolemma associated protein loss-of-function, reduction in rare C, F 23064965 INa BrS16 AD 19q13.33 TRPM4 transient receptor potential cation loss-of-function <2% C, F 23382873 channel subfamily M member 4 BrS20 AD 12p11.21 PKP2 Plakophilin 2 reduced INa rare C, F, S 24352520 Potassium BrS21 AD 12p12.1 ABCC9 SUR2 (ATP binding cassette gain-of-function Increased rare C, F, S 24439875 subfamily C member 9, forms ATP- IKATP sensitive potassium channels) BrS6 AD 11q13.4 KCNE3 MiRP2 (potassium voltage-gated gain-of-function, increased <2% C, F, S 19122847 channel subfamily E regulatory Ito subunit 3) BrS8 AD 7q35-36 KCNH2 Kv11.1 (hERG, potassium voltage- gain-of-function, increased <2% C, F, S 24400717 gated channel subfamily H member IKr 2) BrS9 AD 12p12.1 KCNJ8 Kir6.1 (potassium voltage-gated gain-of-function, increased rare C, F 20558321 channel subfamily J, member 8) IKATP BrS14 AD 15q24.1 HCN4 hyperpolarization activated cyclic loss-of-function, reduced If rare C, F 19165230, nucleotide gated potassium channel 4 (pacemaker current) 22840528 BrS13 AD 1p13.2 KCND3 Kv4.3 (potassium voltage-gated gain-of-function, increased rare C, F 21349352 channel subfamily D member 3) Ito BrS12 XD Xq23 KCNE5 KCNE1L (potassium voltage-gated gain-of-function, increased rare C, F 21493962 channel subfamily E regulatory Ito subunit 5) Calcium BrS10 AD 7q21.11 CACNA2D1 calcium voltage-gated channel loss-of-function rare C, F 20817017 auxiliary subunit alpha 2 delta 1 BrS with Calcium BrS3/SQTS4 AD 12p13.3 CACNA1C Cav1.2 (calcium voltage-gated loss-of-function, reduced ICaL <2% (BrS) C, F, S 17224476 shortened channel subunit alpha1 C) QT interval BrS4/SQTS5 AD 10p12.33- CACNB2b Cavb2 (calcium voltage-gated channel loss-of-function, reduced ICaL <2% (BrS) C, F, S 17224476 p12.31 auxiliary subunit beta 2) SQTS Potassium SQTS1 AD 7q36.1 KCNH2 Kv11.1 (hERG, potassium voltage- gain-of-function, increased 18-35% C, F, S 14676148 gated channel subfamily H member IKr 2) SQTS2 AD 11p15.5-p15.4 KCNQ1 Kv7.1 (potassium voltage-gated gain-of-function, increased <5% C, F 15159330 channel subfamily Q member 1) IKs SQTS3 AD 17q24.3 KCNJ2 Kir2.1 (potassium voltage-gated gain-of-function, increased <5% C, F, S 15761194 channel subfamily J member 2) IK1 ‡ Calcium SQTS6 AD 7q21.11 CACNA2D1 calcium voltage-gated channel loss-of-function, reduced ICaL rare C, F 21383000 auxiliary subunit alpha2 delta 1 PCCD Sodium - AD 3p22.2 SCN5A Nav1.5 (sodium voltage-gated loss-of-function, reduced INa 5% C, F, S 10471492 channel alpha subunit 5) - AD 19q13.11 SCN1B Navb1 (sodium voltage-gated channel Loss-of-function, reduced INa rare C, F, S 18464934 beta subunit 1) - AD 3p22.2 SCN10A Nav1.8 (sodium voltage-gated loss-of-function, reduced INa rare C, F 24642470 channel alpha subunit 10, modulate the activity of Nav1.5) Calcium - AD 19q13.33 TRPM4 Transient receptor potential cation Either loss- or gain-of- rare C, F, S 19726882, channel subfamily M member 4 function, reduced/ increased 27207958, TRPM4 current 26820365, 20562447 Potassium - AD 6p21.2 KCNK17 K2P potassium channel TASK-4 gain-of-function, increased rare C, F 24972929 (Potassium channel subfamily K TASK-4 current member 17) Gap junction - AD 1q21.2 GJA5 connexin-40 Reduction of junctional rare C, F 22247482 protein conductance The level of evidence supporting pathogenic role of mutations in respective genes is classified as follows: clinical data (C), when rare mutations have been identified in patients with the respective phenotype; functional data (F), when molecular characterization has been supportive for damaging effect of mutations on the gene or gene product; segregation data (S), if co-segregation with disease in affected family members has been reported. The assigned phenotype numbers in BrS and PCCD are for categorization purposes only and have not been consistently reported. Although all these genes have been reported as implicated in selected inherited arrhythmia syndromes, available information in many genes is insufficient and their contribution remain to be confirmed ‡ Though mutations in CACNA2D1 have been reported to cause electrophysiological alterations responsible for short QT syndrome, these results have been later reported as irreproducible by several groups. ABS, ankyrin-B syndrome; AD, autosomal dominant; AR, autosomal recessive; ATS, Andersen-Tawil syndrome; BrS, Brugada syndrome; CPVT, Catecholaminergic polymorphic ventricular tachycardia; JLNS, Jervell-Lange-Nielsen syndrome; LQTS, Long-QT syndrome; PCCD, Progressive cardiac conduction disease; RWS, Romano-Ward syndrome; SQTS, Short-QT syndrome; TS, Timothy syndrome; XD, X-linked dominant.
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