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Overall detection rate of likely pathogenic and pathogenic variants and variants of unknown significance using large diagnostic gene panels is 61% and 44% for cardiomyopathies and primary arrhythmia syndromes respectively.
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The majority of detected variants in cardiogenetic gene panels is still classified as variant of unknown significance.
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Larger gene panels can increase the detection rate of pathogenic variants, but mainly increase the frequency of variants with unknown pathogenicity and of multiple variants.
Introduction
Methods
Study population and clinical evaluation
Next-generation sequencing (NGS) gene panels
Gene panel | Genes | Patients tested (n) |
---|---|---|
Arrhythmia panel version 1 (43 genes) |
ABCC9, AKAP9, ANK2, CACNA1C, CACNA1D, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CASQ2, CAV3, DPP6 (only position c.-340), GJA5, GPD1L, HCN4, KCNA5, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LAMP2, LMNA, NPPA, PKP2, PLN, PRKAG2, RANGRF, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, TNNT2, TRDN, TRPM4
| 170 |
Arrhythmia panel version 2 (47 genes) | Version 1 + ASPH, JPH2, SCN2B, SLMAP | 90 |
Arrhythmia panel version 3 (48 genes) | Version 2 + SCN10A | 308 |
Arrhythmia panel version 4 (49 genes) | Version 3 + NKX2-5 | 199 (150 incl. CNV) |
Arrhythmia panel version 5 (50 genes) | Version 4 + PPA2 | 172 |
Cardiomyopathy panel version 1 (23 genes) |
ACTC1, CSRP3, DES, EMD, GLA, LAMP2, LDB3, LMNA, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, SCN5A, SGCD
a
, TAZ, TCAP, TNNC1, TNNI3, TNNT2, TPM1, VCL
| 325 |
Cardiomyopathy panel version 2 (41 genes) | Version 1 + ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, DSC2, DSG2, DSP, FHL1, JPH2, JUP, MYH6, MYOZ2, MYPN, PKP2, RBM20, TMEM43, TTR | 261 |
Cardiomyopathy panel version 3 (46 genes) | Version 2 + CTNNA3, LAMA4, MIB1, NEXN, PRDM16 | 188 |
Cardiomyopathy panel version 4 (47 genes) | Version 3 + TTN | 347 |
Cardiomyopathy panel version 5 (50 genes) | Version 4 + ALPK3, FHL2, HCN4 | 603 (206 incl. CNV) |
Cardiomyopathy panel version 6 (53 genes) | Version 5 + CDH2, FLNC, PPA2 | 246 |
Statistical analysis
Results
Arrhythmia gene panel
Diagnosis | Patients | Variants | Highest pathogenicity class | Multiple | Additional information | ||
---|---|---|---|---|---|---|---|
Total | Class 5 | Class 4 | Class 3 | ||||
In the arrhythmia gene panel in 572 patients with the most common indications | |||||||
Brugada syndrome | 42 | 24 (57.1%) | 4 (9.5%) | 0 (0%) | 23 (54.8%) | 13 | |
LQTS | 65 | 35 (53.8%) | 7 (10.8%) | 5 (7.7%) | 23 (35.4%) | 11 | |
CPVT | 38 | 23 (60.5%) | 0 (0%) | 5 (13.2%) | 18 (47.4%) | 8 | |
SCA/SCD | 6 | 2 (33.3%) | 0 (0%) | 0 (0%) | 2 (33.3%) | 0 | |
UA | 421 | 190 (45.1%) | 17 (4.0%) | 16 (3.8%) | 155 (36.8%) | 48 | Two with risk factor (c.253G > A; p.(Asp85Asn) in KCNE1) |
In the cardiomyopathy gene panel in 1,281 patients with the most common indications | |||||||
HCM | 453 | 319 (70.4%) | 70 (15.5%) | 27 (6.0%) | 222 (49.0%) | 184 | |
DCM | 396 | 271 (68.4%) | 28 (7.1%) | 37 (9.3%) | 206 (52.0%) | 138 | |
NCCM | 67 | 44 (65.7%) | 7 (10.4%) | 5 (7.5%) | 32 (47.8%) | 21 | |
ARVC | 113 | 75 (66.3%) | 19 (16.8%) | 6 (5.3%) | 50 (44.2%) | 36 | |
UCM | 252 | 166 (65.9%) | 22 (8.7%) | 18 (7.1%) | 126 (50.0%) | 86 |
Cardiomyopathy gene panel
Yield and gene panel size
Pathogenicity class | Number of variants < 2015 | Number of variants ≥ 2015 | ||
---|---|---|---|---|
Arrhythmia gene panel
| ||||
Class 5 | 10 | (3.9%) | 22 | (3.2%) |
Class 4 | 11 | (4.2%) | 28 | (4.1%) |
Class 3 | 74 | (28.2%) | 252 | (37.2%) |
Risk factor | 2 | (0.8%) | 2 | (0.3%) |
No variants reported | 164 | (63.3%) | 375 | (55.4%) |
Cardiomyopathy gene panel
| ||||
Class 5 | 86 | (11.1%) | 150 | (12.5%) |
Class 4 | 58 | (7.5%) | 97 | (8.1%) |
Class 3 | 179 | (23.2%) | 624 | (52.1%) |
No variants reported | 450 | (58.2%) | 326 | (27.2%) |