Supplemental Material

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Table S1. Disease specific panels.

DCM panel Gene Gene ENSEMBL Phenotype (Phenotype MIM Allelic Disorder (Phenotype MIM Location RefSeq Symbol Description Transcript ID Number) Number) ATP binding cassette NM_005691. Cardiomyopathy, dilated, 1O ABCC9 12p12.1 ENST00000261201.8 subfamily C 3 (608569) member 9 Cardiomyopathy, hypertrophic, 11 alpha NM_005159. Cardiomyopathy, dilated, 1R ACTC1 15q11-q14 ENST00000290378.5 (612098)/Left ventricular noncompaction 4 cardiac muscle 1 4 (613424) (613424) Cardiomyopathy, dilated, 1AA, Cardiomyopathy, hypertrophic, 23, with or ACTN2 1q42-q43 alpha 2 NM_001103. ENST00000366578.5 with or without LVNC without LVNC (612158) 3 (612158) 10q25.2- BCL2 associated NM_004281. Cardiomyopathy, dilated, 1HH BAG3 ENST00000369085.7 Myopathy, myofibrillar, 6 (612954) q26.2 athanogene 3 3 (613881) 11q22.3- Crystallin alpha NM_001885. Cardiomyopathy, dilated, 1II CRYAB ENST00000616970.4 Myopathy, myofibrillar, 2 (608810) q23.1 B 2 (615184) NM_001927. Cardiomyopathy, dilated, 1I DES 2q35 ENST00000373960.3 Myopathy, myofibrillar, 1 (601419) 3 (604765) NM_004006. Cardiomyopathy, dilated, 3B DMD Xp21.2 ENST00000357033.8 Duchenne muscular dystrophy (310200) 2 (302045) NM_001943. Cardiomyopathy, dilated, 1BB Arrhythmogenic right ventricular DSG2 18q12.1 Desmoglein 2 ENST00000261590.12 4 (612877) dysplasia 10 (610193) with NM_004415. Arrhythmogenic right ventricular DSP 6p24 ENST00000379802.7 woolly hair, keratoderma, and 3 dysplasia 8 (607450) tooth agenesis (615821) Muscular dystrophy-dystroglycanopathy NM_001079 Cardiomyopathy, dilated, 1X FKTN 9q31-q33 Fukutin ENST00000602661.5 (congenital with brain and eye anomalies), 802.1 (611615) type A, 4 (253800)

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Laminin subunit NM_002290. Cardiomyopathy, dilated, 1JJ LAMA4 6q21 ENST00000522006.5 alpha 4 4 (615235) NM_001080 Cardiomyopathy, dilated, 1C, Cardiomyopathy, hypertrophic, 24 10q22.3- LIM domain 116.1 ENST00000372066.7 LDB3 with or without LVNC (601493) / Myopathy, myofibrillar, 4 q23.2 binding 3 NM_007078. ENST00000361373.8 (601493) (609452) 2 1q21.2- NM_170707. Cardiomyopathy, dilated, 1A Emery-Dreifuss muscular dystrophy 2, LMNA A/C ENST00000368300.8 q21.3 3 (115200) autosomal dominant (181350) binding Cardiomyopathy, hypertrophic, 4 MYBPC NM_000256. Cardiomyopathy, dilated, 1MM 11p11.2 C, ENST00000545968.5 (115197) / Left ventricular noncompaction 3 3 (615396) cardiac 10 (615396) Myosin heavy NM_002471. Cardiomyopathy, dilated, 1EE Cardiomyopathy, hypertrophic, 14 MYH6 14q12 ENST00000405093.7 chain 6 3 (613252) (613251) Myosin heavy NM_000257. Cardiomyopathy, dilated, 1S Cardiomyopathy, hypertrophic, 1 MYH7 14q12 ENST00000355349.3 chain 7 3 (613426) (192600) NM_032578. Cardiomyopathy, dilated, 1KK Cardiomyopathy, hypertrophic, 22 MYPN 10q21.3 Myopalladin ENST00000358913.9 3 (615248) (615248) Nexilin F-actin NM_144573. Cardiomyopathy, dilated, 1CC Cardiomyopathy, hypertrophic, 20 NEXN 1p31.1 ENST00000334785.11 binding protein 3 (613122) (613876) NM_002667. Cardiomyopathy, dilated, 1P Cardiomyopathy, hypertrophic, 18 PLN 6q22.1 Phospholamban ENST00000357525.5 4 (609909) (613874) Raf-1 proto- oncogene, NM_002880. Cardiomyopathy, dilated, 1NN RAF1 3p25 ENST00000251849.8 Noonan syndrome 5 (611553) serine/threonine 3 (615916) kinase RNA binding NM_001134 Cardiomyopathy, dilated, 1DD RBM20 10q25.2 ENST00000369519.3 motif protein 20 363.2 (613172) Sodium voltage- NM_198056. Cardiomyopathy, dilated, 1E Brugada syndrome 1 (601144) / Long SCN5A 3p21 gated channel ENST00000333535.8 2 (601154) QT syndrome-3 (603830) alpha subunit 5 Succinate NM_004168. Cardiomyopathy, dilated, 1GG SDHA 5p15 ENST00000264932.10 Paragangliomas 5 (614165) dehydrogenase 3 (613642)

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complex flavoprotein subunit A Sarcoglycan NM_000337. Cardiomyopathy, dilated, 1L Muscular dystrophy, limb-girdle, SGCD 5q33-q34 ENST00000337851.8 delta 5 (606685) autosomal recessive 6 (601287) C1, 3p21.3- NM_003280. Cardiomyopathy, dilated, 1Z Cardiomyopathy, hypertrophic, 13 TNNC1 slow skeletal ENST00000232975.7 p14.3 2 (611879) (613243) and cardiac type Troponin I3, NM_000363. Cardiomyopathy, dilated, 1FF Cardiomyopathy, hypertrophic, 7 TNNI3 19q13.4 ENST00000344887.9 cardiac type 4 (613286) (613690) NM_001001 Troponin T2, 430.2 ENST00000367318.9 Cardiomyopathy, dilated, 1D Cardiomyopathy, hypertrophic, 2 TNNT2 1q32 cardiac type NM_000364. ENST00000236918.11 (601494) (115195) 3 NM_001018 Cardiomyopathy, dilated, 1Y Cardiomyopathy, hypertrophic, 3 TPM1 15q22.1 1 ENST00000403994.7 005.1 (611878) (115196) NM_001267 Cardiomyopathy, dilated, 1G TTN 2q31 ENST00000589042.5 550.2 (604145) 10q22.1- NM_014000. Cardiomyopathy, dilated, 1W Cardiomyopathy, hypertrophic, 15 VCL ENST00000211998.9 q23 2 (611407) (613255)

HCM panel ENSEMBL Gene Gene Phenotype (Phenotype MIM Location RefSeq Transcript Allelic Disorder (Phenotype MIM Number) Symbol Description Number) ID Actin alpha NM_005 ENST00000 Cardiomyopathy, Cardiomyopathy, dilated, 1R (613424) / Left ventricular ACTC1 15q11-q14 cardiac 159.4 290378.5 hypertrophic, 11 (612098) noncompaction 4 (613424) muscle 1 Cardiomyopathy, Actinin Cardiomyopathy, dilated, 1AA, with or without LVNC ACTN2 1q42-q43 NM_001 ENST00000 hypertrophic, 23, with or alpha 2 (612158) 103.3 366578.5 without LVNC (612158)

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NM_033 ENST00000 Cardiomyopathy, familial Long QT syndrome 9 (611818) / Rippling muscle disease CAV3 3p25 Caveolin 3 337.2 343849.2 hypertrophic (192600) 2 (606072) Cysteine and NM_003 ENST00000 CSRP3 11p15.1 glycine rich Cardiomyopathy, hypertrophic, 12 (612124) 476.4 533783.2 protein 3 Four and a NM_001 ENST00000 FHL1 Xq26 half LIM Emery-Dreifuss muscular dystrophy 6, X-linked (300696) 449.4 370690.7 domains 1 Galactosidas NM_000 ENST00000 GLA Xq22 Fabry disease (301500) e alpha 169.2 218516.3 Junctophilin NM_020 ENST00000 JPH2 20q13.12 Cardiomyopathy, hypertrophic, 17 (613873) 2 433.4 372980.3 Lysosomal NM_002 ENST00000 associated 294.2 200639.8 LAMP2 Xq24 Danon disease (300257) membrane NM_013 ENST00000 protein 2 995.2 371335.4 NM_001 ENST00000 10q22.3- LIM domain 080116.1 372066.7 Cardiomyopathy, Cardiomyopathy, dilated, 1C, with or without LVNC LDB3 q23.2 binding 3 NM_007 ENST00000 hypertrophic, 24 (601493) (601493) / Myopathy, myofibrillar, 4 (609452) 078.2 361373.8 Myosin binding NM_000 ENST00000 Cardiomyopathy, Cardiomyopathy, dilated, 1MM (615396) / Left MYBPC3 11p11.2 protein C, 256.3 545968.5 hypertrophic, 4 (115197) ventricular noncompaction 10 (615396) cardiac Myosin NM_002 ENST00000 Cardiomyopathy, MYH6 14q12 heavy chain Cardiomyopathy, dilated, 1EE (613252) 471.3 405093.7 hypertrophic, 14 (613251) 6 Myosin NM_000 ENST00000 Cardiomyopathy, MYH7 14q12 heavy chain Cardiomyopathy, dilated, 1S (613426) 257.3 355349.3 hypertrophic, 1 (192600) 7 12q23- Myosin light NM_000 ENST00000 MYL2 Cardiomyopathy, hypertrophic, 10 (608758) q24.3 chain 2 432.3 228841.12

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3p21.3- Myosin light NM_000 ENST00000 MYL3 Cardiomyopathy, hypertrophic, 8 (608751) p21.2 chain 3 258.2 292327.4 Myosin light NM_033 MYLK2 20q13.31 chain kinase ENST00000 Cardiomyopathy, hypertrophic, 1, digenic (192600) 118.3 2 375985.4 NM_016 ENST00000 MYOZ2 4q26-q27 Myozenin 2 Cardiomyopathy, hypertrophic, 16 (613838) 599.4 307128.5

NM_032 Cardiomyopathy, MYPN 10q21.3 Myopalladin ENST00000 Cardiomyopathy, dilated, 1KK (615248) 578.3 hypertrophic, 22 (615248) 358913.9 Nexilin F- NM_144 ENST00000 Cardiomyopathy, NEXN 1p31.1 actin binding Cardiomyopathy, dilated, 1CC (613122) 573.3 334785.11 hypertrophic, 20 (613876) protein

NM_002 ENST00000 Cardiomyopathy, PLN 6q22.1 Phospholam Cardiomyopathy, dilated, 1P (609909) 667.4 357525.5 hypertrophic, 18 (613874) ban Protein kinase AMP- activated NM_016 ENST00000 PRKAG2 7q36.1 Cardiomyopathy, hypertrophic 6 (600858) non-catalytic 203.3 287878.8 subunit gamma 2 NM_003 ENST00000 Cardiomyopathy, Muscular dystrophy, limb-girdle, autosomal recessive 7 TCAP 17q12 Titin-cap 673.3 309889.2 hypertrophic, 25 (607487) (601954) Troponin C1,

3p21.3- slow skeletal NM_003 Cardiomyopathy, TNNC1 ENST00000 Cardiomyopathy, dilated, 1Z (611879) p14.3 and cardiac 280.2 hypertrophic, 13 (613243) 232975.7 type

Troponin I3, NM_000 Cardiomyopathy, TNNI3 19q13.4 ENST00000 Cardiomyopathy, dilated, 1FF (613286) cardiac type 363.4 hypertrophic, 7 (613690) 344887.9

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NM_001 ENST00000 Troponin T2, 001430.2 367318.9 Cardiomyopathy, TNNT2 1q32 Cardiomyopathy, dilated, 1D (601494) cardiac type NM_000 ENST00000 hypertrophic, 2 (115195) 364.3 236918.11 Tropomyosin NM_001 ENST00000 Cardiomyopathy, TPM1 15q22.1 Cardiomyopathy, dilated, 1Y (611878) 1 018005.1 403994.7 hypertrophic, 3 (115196)

NM_001 Cardiomyopathy, familial TTN 2q31 Titin ENST00000 Cardiomyopathy, dilated, 1G (604145) 267550.2 hypertrophic, 9 (613765) 589042.5 Transthyreti NM_000 ENST00000 TTR 18q12.1 Amyloidosis, hereditary, transthyretin-related (105210) n 371.3 237014.7

10q22.1- NM_014 Cardiomyopathy, VCL Vinculin ENST00000 Cardiomyopathy, dilated, 1W (611407) q23 000.2 hypertrophic, 15 (613255) 211998.9

RCM panel Phenotype Gene Gene ENSEMBL Location RefSeq (Phenotype MIM Allelic Disorder (Phenotype MIM Number) Symbol Description Transcript ID Number) Cardiomyopathy, dilated, 1I DES 2q35 Desmin NM_001927.3 ENST00000373960.3 (604765)/Myopathy, myofibrillar, 1 (601419) Cardiomyopathy, FLNC 7q32-q35 Ffilamin C NM_001458.4 ENST00000325888.1 familial restrictive 5 Myopathy, myofibrillar, 5 (609524) 2 (617047) Myosin Cardiomyopathy, hypertrophic, 1 (192600) / MYH7 14q12 heavy chain NM_000257.3 ENST00000355349.3 Cardiomyopathy, dilated, 1S (613426) 7 Cardiomyopathy, Cardiomyopathy, hypertrophic, 22 (615248) / MYPN 10q21.3 Myopalladin NM_032578.3 familial restrictive, 4 ENST00000358913.9 Cardiomyopathy, dilated, 1KK (615248) (615248)

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Cardiomyopathy, Troponin I3, Cardiomyopathy, hypertrophic, 7 (613690) / TNNI3 19q13.4 NM_000363.4 familial restrictive, 1 cardiac type ENST00000344887.9 Cardiomyopathy, dilated, 1FF (613286) (115210) Troponin ENST00000367318.9 Cardiomyopathy, NM_001001430. Cardiomyopathy, dilated, 1D (601494) / TNNT2 1q32 T2, cardiac ENST00000236918.1 familial restrictive, 3 2 NM_000364.3 Cardiomyopathy, hypertrophic, 2 (115195) type 1 (612422) Tropomyosi NM_001018005. Cardiomyopathy, hypertrophic, 3 (115196) / TPM1 15q22.1 ENST00000403994.7 n 1 1 Cardiomyopathy, dilated, 1Y (611878)

LVNC panel Gene Gene Phenotype (Phenotype MIM Allelic Disorder (Phenotype Location RefSeq ENSEMBL Transcript ID Symbol Description Number) MIM Number) Cardiomyopathy, Actin alpha Left ventricular noncompaction 4 hypertrophic, 11 (612098) / ACTC1 15q11-q14 NM_005159.4 ENST00000290378.5 cardiac muscle 1 (613424) Cardiomyopathy, dilated, 1R (613424) Cardiomyopathy, dilated, 1I DES 2q35 Desmin NM_001927.3 ENST00000373960.3 (604765) / Myopathy, myofibrillar, 1 (601419) Dystrobrevin Left ventricular noncompaction 1, with or without congenital heart DTNA 18q12 NM_001390.4 ENST00000444659.5 alpha defects (604169) Cardiomyopathy, dilated, 1C, with or without LVNC NM_00108011 10q22.3- LIM domain ENST00000372066.7 Left ventricular noncompaction 3 (601493) / Cardiomyopathy, LDB3 6.1 q23.2 binding 3 ENST00000361373.8 (601493) hypertrophic, 24 (601493) NM_007078.2 / Myopathy, myofibrillar, 4 (609452) Emery-Dreifuss muscular 1q21.2- LMNA Lamin A/C NM_170707.3 ENST00000368300.8 dystrophy 2, autosomal q21.3 dominant (181350) /

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Cardiomyopathy, dilated, 1A (115200) Cardiomyopathy, dilated, Myosin heavy Left ventricular noncompaction 5 1S (613426) / MYH7 14q12 NM_000257.3 ENST00000355349.3 chain 7 (613426) Cardiomyopathy, hypertrophic, 1 (192600) Cardiomyopathy, dilated, Myosin binding MYBPC Left ventricular noncompaction 10 1MM (615396) 11p11.2 protein C, NM_000256.3 ENST00000545968.5 3 (615396) /Cardiomyopathy, cardiac hypertrophic, 4 (115197) PRDM1 1p36.23- PR/SET NM_022114.3 ENST00000270722.9 Left ventricular noncompaction 8 (615373) 6 p33 domain 16 TAZ Xq28 Tafazzin NM_000116.4 ENST00000601016.5 Barth syndrome (302060) NM_00100143 Cardiomyopathy, dilated, 1D Troponin T2, ENST00000367318.9 Left ventricular noncompaction 6 TNNT2 1q32 0.2 (601494) / Cardiomyopathy, cardiac type ENST00000236918.11 (601494) NM_000364.3 hypertrophic, 2 (115195) Cardiomyopathy, dilated, NM_00101800 Left ventricular noncompaction 9 1Y (611878) / TPM1 15q22.1 Tropomyosin 1 ENST00000403994.7 5.1 (611878) Cardiomyopathy, hypertrophic, 3 (115196)

ARVC panel Gene Gene ENSEMBL Phenotype (Phenotype MIM Allelic Disorder (Phenotype MIM Location RefSeq Symbol Description Transcript ID Number) Number) NM_013266 ENST000004332 CTNNA3 10q22.2 alpha 3 Arrhythmogenic right ventricular dysplasia, familial, 13 (615616) .3 11.6 Cardiomyopathy, dilated, 1I NM_001927 DES 2q35 Desmin ENST00000373960.3 (604765) / Myopathy, myofibrillar, .3 1 (601419) NM_024422 ENST000002809 DSC2 18q12.1 Desmocollin 2 Arrhythmogenic right ventricular dysplasia 11 (610476) .4 04.10

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NM_001943 ENST000002615 Arrhythmogenic right ventricular Cardiomyopathy, dilated, 1BB DSG2 18q12.1 Desmoglein 2 .4 90.12 dysplasia 10 (610193) (612877)

NM_004415 DSP 6p24 Desmoplakin ENST000003798 Arrhythmogenic right ventricular dysplasia 8 (607450) .3 02.7 Junction NM_002230 ENST000003939 JUP 17q21 Arrhythmogenic right ventricular dysplasia 12 (611528) .3 31.7 Emery-Dreifuss muscular dystrophy 1q21.2- NM_170707 2, autosomal dominant (181350) / LMNA Lamin A/C ENST00000368300.8 q21.3 .3 Cardiomyopathy, dilated, 1A (115200)

NM_004572 PKP2 12p11 2 ENST000000708 Arrhythmogenic right ventricular dysplasia 9 (609040) .3 46.10 Cardiomyopathy, dilated, 1P NM_002667 PLN 6q22.1 ENST00000357525.5 (609909) / Cardiomyopathy, Phospholamban .4 hypertrophic, 18 (613874) Ventricular tachycardia, 1q42.1- Ryanodine NM_001035 ENST000003665 Arrhythmogenic right ventricular RYR2 catecholaminergic polymorphic, 1 q43 receptor 2 .2 74.6 dysplasia 2 (600996) (604772) Transforming NM_003239 ENST000002386 TGFB3 14q24 growth factor Arrhythmogenic right ventricular dysplasia 1 (107970) .4 82.7 beta 3

Transmembrane NM_024334 TMEM43 3p25.1 ENST000003060 Arrhythmogenic right ventricular dysplasia 5 (604400) protein 43 .2 77.4 Cardiomyopathy, dilated, 1G NM_001267 TTN 2q31 Titin ENST00000589042.5 (604145) / Cardiomyopathy, familial 550.2 hypertrophic, 9 (613765)

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Long QT panel Gene ENSEMBL Phenotype (Phenotype MIM Allelic Disorder (Phenotype Location Gene Description RefSeq Symbol Transcript ID Number) MIM Number) NM_005 ENST000003562 AKAP9 7q21-q22 A-kinase anchoring protein 9 ?Long QT syndrome-11 (611820) 751.4 39.7 NM_001 ENST000003570 ANK2 4q25-q27 2 Long QT syndrome 4 (600919) 148.5 77.8 CACNA1 Calcium voltage-gated NM_000 ENST000003996 Brugada syndrome 3 12p13.3 Long QT syndrome 8 (618447) C channel subunit alpha1 C 719.6 55.5 (611875) NM_006 ENST000003569 CALM1 14q24-q31 Calmodulin 1 Long QT syndrome 14 (616247) 888.4 78.8

NM_033 CAV3 3p25 Caveolin 3 ENST000003438 Long QT syndrome 9 (611818) 337.2 49.2 Potassium voltage-gated NM_000 Jervell and Lange-Nielsen KCNE1 21q22.12 channel subfamily E ENST000003992 Long QT syndrome 5 (613695) 219.5 syndrome 2 (612347) regulatory subunit 1 86.2 Potassium voltage-gated NM_172 ENST000002903 KCNE2 21q22.12 channel subfamily E Long QT syndrome 6 (613693) 201.1 10.3 regulatory subunit 2 Potassium voltage-gated 17q23.1- NM_000 Andersen syndrome/ Long QT KCNJ2 channel subfamily J member ENST000002434 q24.2 891.2 syndrome 7 (170390) 2 57.3 Potassium voltage-gated NM_000 ENST000005296 KCNJ5 11q24 channel subfamily J member Long QT syndrome 13 (613485) 890.4 94.5 5 Potassium voltage-gated NM_000 ENST000002621 Short QT syndrome 1 KCNH2 7q35-q36 channel subfamily H member Long QT syndrome 2 (613688) 238.3 86.9 (609620) 2 Potassium voltage-gated Jervell and Lange-Nielsen NM_000 ENST000001558 KCNQ1 11p15.5 channel subfamily Q member Long QT syndrome 1 (192500) syndrome (220400) / Short 218.2 40.10 1 QT syndrome 2 (609621)

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Sodium voltage-gated NM_174 SCN4B 11q23.3 ENST000003247 Long QT syndrome-10 (611819) channel beta subunit 4 934.3 27.8 Sodium voltage-gated NM_198 ENST000003335 Brugada syndrome 1 SCN5A 3p21 Long QT syndrome-3 (603830) channel alpha subunit 5 056.2 35.8 (601144) NM_003 ENST000002173 SNTA1 20q11.2 Syntrophin alpha 1 Long QT syndrome 12 (612955) 098.2 81.2

Brugada panel Gene ENSEMBL Phenotype (Phenotype Allelic Disorder (Phenotype Location Gene Description RefSeq Symbol Transcript ID MIM Number) MIM Number) Calcium voltage-gated channel NM_000 ENST000003996 Brugada syndrome 3 CACNA1C 12p13.3 Long QT syndrome 8 (618447) subunit alpha1 C 719.6 55.5 (611875)

Calcium voltage-gated channel NM_201 Brugada syndrome 4 CACNB2 10p12 ENST000003773 auxiliary subunit beta 2 590.2 (611876) 29.9 Glycerol-3-phosphate dehydrogenase NM_015 ENST000002825 Brugada syndrome 2 GPD1L 3p22.3 1 like 141.3 41.9 (611777) Hyperpolarization activated cyclic NM_005 ENST000002619 Brugada syndrome 8 HCN4 15q24-q25 nucleotide gated potassium channel 4 477.2 17.3 (613123)

Potassium voltage-gated channel NM_005 ?Brugada syndrome 6 KCNE3 11q13-q14 ENST000003101 subfamily E regulatory subunit 3 472.4 (613119) 28.8

Potassium voltage-gated channel NM_004 Brugada syndrome 9 KCND3 1p13.3 ENST000003159 subfamily D member 3 980.4 (616399) 87.6 Sodium voltage-gated channel beta NM_001 ENST000006385 Brugada syndrome 5 SCN1B 19q13.1 subunit 1 037.4 36.1 (612838) Sodium voltage-gated channel beta NM_018 ENST000003927 Brugada syndrome 7 SCN3B 11q23.3 subunit 3 400.3 70.6 (613120)

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Sodium voltage-gated channel alpha NM_198 ENST000003335 Brugada syndrome 1 SCN5A 3p21 Long QT syndrome-3 (603830) subunit 5 056.2 35.8 (601144) Transient receptor potential cation NM_017 ENST000002528 Progressive familial heart block, TRPM4 19q13.33 channel subfamily M member 4 636.3 26.9 type IB (604559)

CPVT panel Gene Locatio ENSEMBL Allelic Disorder (Phenotype MIM Gene Description RefSeq Phenotype (Phenotype MIM Number) Symbol n Transcript ID Number) 14q24- NM_006 ENST000003569 Ventricular tachycardia, catecholaminergic CALM1 Calmodulin 1 Long QT syndrome 14 (616247) q31 888.4 78.8 polymorphic, 4 (614916) 1p13.3- NM_001 ENST000002614 CASQ2 Calsequestrin 2 Ventricular tachycardia, catecholaminergic polymorphic, 2 (611938) p11 232.3 48.5

G protein subunit NM_002 GNAI2 3p21 ENST000003136 Ventricular tachycardia, idiopathic (192605) alpha i2 070.3 01.10 Potassium 17q23.1 voltage-gated NM_000 Andersen syndrome/ Long QT KCNJ2 ENST00000243457.3 -q24.2 channel subfamily 891.2 syndrome 7 (170390) J member 2 1q42.1- Ryanodine NM_001 ENST000003665 Ventricular tachycardia, catecholaminergic Arrhythmogenic right ventricular RYR2 q43 receptor 2 035.2 74.6 polymorphic, 1 (604772) dysplasia 2 (600996)

NM_006 Ventricular tachycardia, catecholaminergic polymorphic, 5, with or without muscle TRDN 6q22.31 Triadin ENST000003342 073.3 weakness (615441) 68.8

Table S2. Extended gene panel for cardiomyopathies and primary arrhythmia syndromes.

Gen Location Gene Description RefSeq Transkript-ID Ensemble p-OMIM Allelic Disorder

ATP binding cassette NM_005691. ENST00000261201.8 Cardiomyopathy, dilated, 1O ABCC9 12p12.1 subfamily C member 9 3 ENST00000261200.8 (608569)

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Cardiomyopathy, Actin alpha cardiac NM_005159. Cardiomyopathy, hypertrophic, hypertrophic, 11 (612098) / ACTC1 15q11-q14 ENST00000290378.5 muscle 1 4 11 612098 Left ventricular noncompaction 4 (613424) Cardiomyopathy, dilated, 1AA, Cardiomyopathy, NM_001103. ACTN2 1q42-q43 ENST00000366578.5 with or without LVNC hypertrophic, 23, with or 3 (612158) without LVNC (612158) A-kinase anchoring NM_005751. ?Long QT syndrome-11 AKAP9 7q21-q22 ENST00000356239.7 protein 9 4 (611820) NM_001148. ANK2 4q25-q27 Ankyrin 2 ENST00000357077.8 Long QT syndrome 4 (600919) 5 10q25.2- BCL2 associated NM_004281. Cardiomyopathy, dilated, 1HH Myopathy, myofibrillar, 6 BAG3 ENST00000369085.7 q26.2 athanogene 3 3 (613881) (612954) Calcium voltage-gated CACNA NM_000719. ENST00000399655.5 12p13.3 channel subunit alpha1 Long QT syndrome 8 (618447) 1C 6 ENST00000347598.8 C Calcium voltage-gated CACNB NM_201590. ENST00000377329.9 10p12 channel auxiliary Brugada syndrome 4 (611876) 2 2 ENST00000324631.11 subunit beta 2 NM_006888. CALM1 14q24-q31 Calmodulin 1 ENST00000356978.8 Long QT syndrome 14 616247 4 Cardiomyopathy, familial NM_033337. hypertrophic (192600) / CAV3 3p25 Caveolin 3 ENST00000343849.2 Long QT syndrome 9 (611818) 2 Rippling muscle disease 2 (606072) 1p13.3- NM_001232. Ventricular tachycardia, catecholaminergic polymorphic, 2 CASQ2 Calsequestrin 2 ENST00000261448.5 p11 3 (611938) 11q22.3- NM_001885. Cardiomyopathy, dilated, 1II Myopathy, myofibrillar, 2 CRYAB Crystallin alpha B ENST00000616970.4 q23.1 2 (615184) (608810) Cysteine and glycine NM_003476. Cardiomyopathy, hypertrophic, CSRP3 11p15.1 ENST00000533783.2 rich protein 3 4 12 (612124)

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CTNNA NM_013266. 10q22.2 Catenin alpha 3 ENST00000433211.6 Arrhythmogenic right ventricular dysplasia, familial, 13 (615616) 3 3 NM_001927. Cardiomyopathy, dilated, 1I DES 2q35 Desmin ENST00000373960.3 3 604765 NM_004006. Cardiomyopathy, dilated, 3B Duchenne muscular dystrophy DMD Xp21.2 Dystrophin ENST00000357033.8 2 (302045) (310200) NM_024422. 4 ENST00000280904.10 DSC2 18q12.1 Desmocollin 2 Arrhythmogenic right ventricular dysplasia 11 (610476) NM_004949. ENST00000251081.6 3 Arrhythmogenic right NM_001943. Cardiomyopathy, dilated, 1BB DSG2 18q12.1 Desmoglein 2 ENST00000261590.12 ventricular dysplasia 10 4 (612877) (610193) Arrhythmogenic right Dilated cardiomyopathy with NM_004415. DSP 6p24 Ddesmoplakin ENST00000379802.7 ventricular dysplasia 8 woolly hair, keratoderma, and 3 (607450) tooth agenesis (615821) NM_001390. Left ventricular noncompaction 1, with or without congenital DTNA 18q12 Dystrobrevin alpha ENST00000444659.5 4 heart defects (604169) NM_000117. EMD Xq28 Eemerin ENST00000369842.8 Emery-Dreifuss muscular dystrophy 1, X-linked (310300) 2 Four and a half LIM NM_001449. ENST00000370690.7 FHL1 Xq26 Emery-Dreifuss muscular dystrophy 6, X-linked (300696) domains 1 4 ENST00000394155.6 Muscular dystrophy- dystroglycanopathy NM_0010798 Cardiomyopathy, dilated, 1X FKTN 9q31-q33 Fukutin ENST00000602661.5 (congenital with brain and eye 02.1 (611615) anomalies), type A, 4 (253800) NM_001458. Cardiomyopathy, familial FLNC 7q32-q35 C ENST00000325888.12 4 restrictive 5 (617047) GATAD GATA zinc finger NM_021167. ?Cardiomyopathy, dilated, 2B 7q21-q22 ENST00000287957.3 1 domain containing 1 4 (614672)

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NM_000169. GLA Xq22 Galactosidase alpha ENST00000218516.3 Fabry disease (301500) 2 G protein subunit alpha NM_002070. Ventricular tachycardia, GNAI2 3p21 ENST00000313601.10 i2 3 idiopathic (192605) Glycerol-3-phosphate NM_015141. Brugada syndrome 2 GPD1L 3p22.3 ENST00000282541.9 dehydrogenase 1 like 3 (611777) Hyperpolarization activated cyclic NM_005477. HCN4 15q24-q25 ENST00000261917.3 Brugada syndrome 8 (613123) nucleotide gated 2 potassium channel 4 NM_020433. Cardiomyopathy, hypertrophic, JPH2 20q13.12 Junctophilin 2 ENST00000372980.3 4 17 (613873) NM_002230. JUP 17q21 Junction plakoglobin ENST00000393931.7 Arrhythmogenic right ventricular dysplasia 12 611528 3 Potassium voltage-gated NM_004980. KCND3 1p13.3 channel subfamily D ENST00000315987.6 Brugada syndrome 9 (616399) 4 member 3 Potassium voltage-gated NM_000219. KCNE1 21q22.12 channel subfamily E ENST00000399286.2 Long QT syndrome 5 (613695) 5 regulatory subunit 1 Potassium voltage-gated NM_172201. KCNE2 21q22.12 channel subfamily E ENST00000290310.3 Long QT syndrome 6 (613693) 1 regulatory subunit 2 Potassium voltage-gated NM_005472. ?Brugada syndrome 6 KCNE3 11q13-q14 channel subfamily E ENST00000310128.8 4 (613119) regulatory subunit 3 Potassium voltage-gated NM_000238. KCNH2 7q35-q36 channel subfamily H ENST00000262186.9 Long QT syndrome 2 (613688) 3 member 2 Potassium voltage-gated 17q23.1- NM_000891. Andersen syndrome/ Long QT KCNJ2 channel subfamily J ENST00000243457.3 Short QT syndrome 3 609622 q24.2 2 syndrome 7 (170390) member 2

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Potassium voltage-gated NM_000890. KCNJ5 11q24 channel subfamily J ENST00000529694.5 Long QT syndrome 13 613485 4 member 5 Potassium voltage-gated NM_000218. KCNQ1 11p15.5 channel subfamily Q ENST00000155840.10 Long QT syndrome 1 (192500) 2 member 1 NM_002290. ENST00000522006.5 Cardiomyopathy, dilated, 1JJ LAMA4 4 ENST00000230538.11 (615235) ENST00000200639.8 Lysosomal associated NM_002294. LAMP2 Xq24 ENST00000371335.4 Danon disease (300257) membrane protein 2 2 ENST00000434600.6 NM_007078. ENST00000361373.8 10q22.3- 2 LDB3 LIM domain binding 3 ENST00000372066.7 Cardiomyopathy, dilated, 1C, with or without LVNC (601493) q23.2 NM_0010801 ENST00000263066.10 16.1 Emery-Dreifuss muscular 1q21.2- NM_170707. Cardiomyopathy, dilated, 1A LMNA Lamin A/C ENST00000368300.8 dystrophy 2, autosomal q21.3 3 (115200) dominant (181350) Cardiomyopathy, dilated, MYBPC Myosin binding protein NM_000256. Cardiomyopathy, hypertrophic, 1MM (615396) / Left 11p11.2 ENST00000545968.5 3 C, cardiac 3 4 (115197) ventricular noncompaction 10 (615396) NM_002471. Cardiomyopathy, dilated, 1EE MYH6 14q12 Myosin heavy chain 6 ENST00000405093.7 3 613252 NM_000257. Cardiomyopathy, hypertrophic, Cardiomyopathy, dilated, 1S MYH7 14q12 Myosin heavy chain 7 ENST00000355349.3 3 1 (192600) (613426) 12q23- NM_000432. Cardiomyopathy, MYL2 2 ENST00000228841.12 q24.3 3 hypertrophic, 10 608758 3p21.3- NM_000258. Cardiomyopathy, hypertrophic, MYL3 Myosin light chain 3 ENST00000292327.4 p21.2 2 8 (608751) Myosin light chain NM_033118. MYLK2 20q13.31 ENST00000375985.4 Cardiomyopathy, hypertrophic, 1, digenic (192600) kinase 2 3

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NM_016599. Cardiomyopathy, hypertrophic, MYOZ2 4q26-q27 Myozenin 2 ENST00000307128.5 4 16 (613838) NM_032578. Cardiomyopathy, hypertrophic, Cardiomyopathy, dilated, 1KK MYPN 10q21.3 Myopalladin ENST00000358913.9 3 22 (615248) (615248) Nexilin F-actin binding NM_144573. Cardiomyopathy, dilated, 1CC Cardiomyopathy, NEXN 1p31.1 ENST00000334785.11 protein 3 (613122) hypertrophic, 20 (613876) NM_004572. PKP2 12p11 Plakophilin 2 ENST00000070846.10 Arrhythmogenic right ventricular dysplasia 9 609040 3 NM_002667. Cardiomyopathy, dilated, 1P Cardiomyopathy, PLN 6q22.1 Phospholamban ENST00000357525.5 4 609909 hypertrophic, 18 (613874) PRDM1 1p36.23- NM_022114. Left ventricular noncompaction PR/SET domain 16 ENST00000270722.9 6 p33 3 8 (615373) Protein kinase AMP- PRKAG NM_016203. Cardiomyopathy, hypertrophic 7q36.1 activated non-catalytic ENST00000287878.8 2 3 6 (600858) subunit gamma 2 Raf-1 proto-oncogene, NM_002880. Cardiomyopathy, dilated, 1NN RAF1 3p25 ENST00000251849.8 serine/threonine kinase 3 615916 RNA binding motif NM_0011343 Cardiomyopathy, dilated, 1DD RBM20 10q25.2 ENST00000369519.3 protein 20 63.2 (613172) 1q42.1- NM_001035. Ventricular tachycardia, catecholaminergic polymorphic, 1 RYR2 Ryanodine receptor 2 ENST00000366574.6 q43 2 604772 Sodium voltage-gated NM_001037. ENST00000638536.1 SCN1B 19q13.1 Brugada syndrome 5 (612838) channel beta subunit 1 4 ENST00000415950.4 Sodium voltage-gated NM_018400. SCN3B 11q23.3 ENST00000392770.6 Brugada syndrome 7 (613120) channel beta subunit 3 3 Sodium voltage-gated NM_174934. Long QT syndrome-10 SCN4B 11q23.3 ENST00000324727.8 channel beta subunit 4 3 (611819) Sodium voltage-gated NM_198056. Brugada syndrome 1 (601144) / Cardiomyopathy, dilated, 1E SCN5A 3p21 ENST00000333535.8 channel alpha subunit 5 2 Long QT syndrome-3 (603830) (601154) Succinate NM_004168. Cardiomyopathy, dilated, 1GG SDHA 5p15 dehydrogenase complex ENST00000264932.10 Paragangliomas 5 (614165) 3 (613642) flavoprotein subunit A

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Muscular dystrophy, limb- NM_000337. Cardiomyopathy, dilated, 1L SGCD 5q33-q34 ENST00000337851.8 girdle, autosomal recessive 6 5 (606685) (601287) NM_003098. SNTA1 20q11.2 Syntrophin alpha 1 ENST00000217381.2 Long QT syndrome 12 (612955) 2 NM_000116. TAZ Xq28 Tafazzin ENST00000601016.5 Barth syndrome (302060) 4 Muscular dystrophy, limb- NM_003673. Cardiomyopathy, hypertrophic, TCAP 17q12 Titin-cap ENST00000309889.2 girdle, autosomal recessive 7 3 25 (607487) (601954) Transforming growth NM_003239. TGFB3 14q24 ENST00000238682.7 Arrhythmogenic right ventricular dysplasia 1 107970 factor beta 3 4 TMEM4 Transmembrane protein NM_024334. 3p25.1 ENST00000306077.4 Arrhythmogenic right ventricular dysplasia 5 604400 3 43 2 3p21.3- Troponin C1, slow NM_003280. Cardiomyopathy, dilated, 1Z Cardiomyopathy, TNNC1 ENST00000232975.7 p14.3 skeletal and cardiac type 2 (611879) hypertrophic, 13 (613243) Troponin I3, cardiac NM_000363. Cardiomyopathy, dilated, 1FF Cardiomyopathy, TNNI3 19q13.4 ENST00000344887.9 type 4 (613286) hypertrophic, 7 (613690) Troponin T2, cardiac NM_0010014 ENST00000367318.9 Cardiomyopathy, dilated, 1D Cardiomyopathy, TNNT2 1q32 type 30.2 ENST00000236918.11 (601494) hypertrophic, 2 (115195) NM_0010180 ENST00000403994.7 Cardiomyopathy, hypertrophic, Cardiomyopathy, dilated, 1Y TPM1 15q22.1 Tropomyosin 1 05.1 ENST00000559556.5 3 (115196) (611878) NM_006073. Ventricular tachycardia, catecholaminergic polymorphic, 5, with TRDN 6q22.31 Triadin ENST00000334268.8 3 or without muscle weakness (615441) Transient receptor NM_017636. TRPM4 19q13.33 potential cation channel ENST00000252826.9 Progressive familial heart block, type IB (604559) 3 subfamily M member 4 NM_0012675 ENST00000589042.5 Cardiomyopathy, dilated, 1G TTN 2q31 Titin 50.2 ENST00000342992.10 (604145) NM_000371. TTR 18q12.1 Transthyretin ENST00000237014.7 Amyloidosis, hereditary, transthyretin-related (105210) 3

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10q22.1- NM_014000. Cardiomyopathy, dilated, 1W Cardiomyopathy, VCL Vinculin ENST00000211998.9 q23 2 (611407) hypertrophic, 15 (613255)

Table S3. Detected variants in without a p-OMIM number at the time of testing.

Popmax HGV gnomAD ACMG Pathogenicity Pat. # Diagnosis Gene REFSEQ HGVSc Consequence Filtering ACMG Rules Sp AF Class Clues AF Genes with evidence of pathogenic relevance Identification of variant of PM1, PM2, PP4 p.(Pro MYLK3 mutations MYL NM_1824 c.2042C unknown (no 15 DCM 681Le missense variant in familial dilated K3 93.2 >T significanc literature/databas u) cardiomyopathy e* e report) [1] TRIM NM_0325 c.739C> p.(Gln nonsense likely 45 HCM 0.0006787 0.0003963 PVS1, PP4, PP5 [2,3] 63 88.3 T 247*) variant pathogenic Not well studied candidate genes Development of p.(Pro dilated ARN NM_0012 c.1588C 6 HCM 530Al missense variant n/a n/a cardiomyopathy TL 97719.1 >G a) in Bmal1-deficient mice [4] OBSCN Mutations Associated with p.(Le Dilated OBSC NM_0528 c.8243T missense 0.0000202 0.0000171 u2748 n/a n/a Cardiomyopathy N 43.3 >C variant 0 2 Pro) and 1 ARVC Haploinsufficiency [5] Titin-associated p.(Glu MYO NM_0038 c.776A> missense 0.0000183 0.0000114 Protein, 259Gl n/a n/a M1 03.3 G variant 5 7 Association with y) HCM [6] p.(Glu Stk38 Modulates STK3 NM_0072 c.222du 47 DCM 75Arg frameshift variant n/a n/a Rbm24 Protein 8 71.3 p fs*16) Stability to

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Regulate Assembly in Cardiomyocytes [7] p.(Ser Association with Brugada SLM NM_0071 c.1663A missense 0.0000079 0.0000189 48 555Gl n/a n/a Brugada syndrome AP 59.4 >G variant 60 8 y) syndrome [8] * : VUS favor pathogenic, n/a: not applicable.

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Figure S1. Variant classification scheme proposed in this study. (VUS: variants of uncertain significance).

Figure S2. Variants of interests according to molecular function in different patient sub-cohorts.

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Figure S3. Pedigree of the consanguineous family (origin: Christian Arabs) with the TRIM63 variant.

References

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