Table 1.
Gene characteristics and evidence for role in DCM pathogenesis
| Gene | Protein | Gene group |
RVIS | pLI score |
Z score |
Genetic data* |
In vitro defects |
Animal model† |
Other phenotypes |
|---|---|---|---|---|---|---|---|---|---|
| MYH7 | Myosin heavy chain 7 | A | 0.28 | 0.00 | 6.54 | +++ | Yes | +++ | HCM, RCM, LVNC, CHD, DM, MSM, SPM |
| DSP | Desmoplakin | A | 1.32 | 1.00 | 0.91 | +++ | Yes | +++ | ARVC, LVNC, palmoplantar keratoderma, skin-fragility woolly hair syndrome |
| SCN5A | Cardiac sodium channel | A | 1.99 | 1.00 | 2.53 | +++ | Yes | +++ | CD, AF, LQTS, BS, VF, LVNC |
| LMNA | Lamin A/C | A | 9.96 | 0.99 | 3.37 | +++ | Yes | +++ | CD, EDMD, >10 additional phenotypes/overlap syndromes. |
| LDB3 | LIM domain binding protein 3 | A | 10.16 | 0.00 | 0.32 | +++ | Yes | +++ | HCM, LVNC, ARVC, MM |
| DMD | Dystrophin | A | 11.28 | 1.00 | −4.82 | +++ | Yes | +++ | DMD, BMD |
| DES | Desmin | A | 21.56 | 0.00 | 2.34 | +++ | Yes | +++ | RCM, ARVC, HCM, CD, MM, LGMD-2R, NSS |
| TPM1 | Tropomyosin α-1 chain | A | 25.15 | 0.80 | 3.42 | +++ | Yes | +++ | HCM, RCM, LVNC |
| TNNC1 | Troponin C | A | 39.68 | 0.51 | 2.22 | +++ | Yes | +++ | HCM |
| TNNT2 | Troponin T | A | 41.64 | 0.01 | 1.54 | +++ | Yes | +++ | HCM, RCM, LVNC |
| BAG3 | BCL-2 associated athanogene | A | 62.14 | 0.53 | −1.01 | +++ | Yes | +++ | MM |
| PLN | Phospholamban | A | 62.38 | 0.11 | 0.57 | +++ | Yes | +++ | HCM, ARVC |
| RBM20 | RNA-binding protein 20 | A | 90.98 | NA | NA | +++ | Yes | + | |
| TTN | Titin | A | 98.04 | 0.00 | −5.48 | +++ | Yes | ++ | HCM, ARVC, RCM, LVNC, CM, CNM, HMERF, LGMD-2J, TMD |
| VCL | Vinculin | B | 2.23 | 0.99 | 3.11 | ++ | Yes | ++ | HCM |
| LAMA4 | Laminin subunit α-4 | B | 4.68 | 0.00 | −1.14 | + | Yes | ++ | |
| ILK | Integrin-linked protein kinase | B | 14.97 | 0.04 | 0.96 | + | Yes | ++ | |
| MYBPC3 | Cardiac myosin binding protein 3 | B | 20.54 | 0.00 | 0.69 | ++ | Yes | ++ | HCM, LVNC |
| CSRP3 | Muscle LIM protein | B | 28.93 | 0.00 | −0.66 | ++ | Yes | ++ | HCM |
| CRYAB | αβ-crystallin | B | 35.42 | 0.01 | 0.38 | ++ | Yes | +++ | MM, DM, cataracts |
| ACTC1 | Cardiac actin | B | 38.28 | 0.95 | 5.25 | ++ | Yes | +++ | HCM, RCM, LVNC, CHD |
| NEXN | Nexilin | B | 50.34 | 0.00 | −1.32 | ++ | NA | ++ | HCM, CHD |
| TAZ | Tafazzin | B | 59.76 | 0.97 | 2.42 | +++ | Yes | ++ | Barth syndrome (may present as infantile X-linked DCM), LVNC, EFE |
| LAMP2 | Lysosome-associated membrane glycoprotein 2 | B | 61.73 | 0.95 | 0.41 | ++ | Yes | + | Danon disease (may present as HCM or DCM) |
| TNNI3 | Troponin I | B | 64.11 | 0.17 | 1.88 | ++ | Yes | + | HCM, RCM, AF |
| ANKRD1 | Cardiac ankyrin repeat protein | B | 65.76 | 0.00 | −0.01 | ++ | Yes | No | HCM, CHD |
| DSG2 | Desmoglein-2 | B | 98.32 | 0.00 | −1.20 | ++ | NA | +++ | ARVC |
| MYH6 | Myosin heavy chain 6 | C | 0.66 | 0.00 | 2.87 | ++ | NA | ++§ | HCM, CHD, SSS |
| ABCC9 | KATP channel SUR2A subunit | C | 1.82 | 0.00 | 4.89 | + | Yes | ++ | AF, BS, Cantu syndrome, coronary vasospasm |
| ACTN2 | α-actinin | C | 2.47 | 1.00 | 1.76 | + | Yes | + | HCM |
| PDLIM3 | PDZ and LIM domain protein 3 | C | 20.70 | 0.00 | −0.04 | + | NA | ++ | |
| SGCD | δ - sarcoglycan | C | 34.32 | 0.00 | −0.23 | ++ | Yes | ++ | LGMD-2F |
| SYNE1 | Nesprin-1 | C | 41.65 | 0.00 | −0.95 | + | Yes | + | EDMD, cerebellar ataxia, autism, arthrogryposis |
| FXN | Frataxin | C | 76.67 | 0.82 | 0.47 | + | NA | ++ | Friedreich’s ataxia (may develop LVH + late DCM) |
| CAV3 | Caveolin-3 | C | 77.70 | 0.34 | 1.19 | + | Yes | ++ | HCM, LQTS, SIDS, LGMD-1C, RMD-2, DM, HCK |
| TCAP | Telethonin | C | 78.28 | 0.08 | 0.45 | + | Yes | + | HCM, LGMD-2G |
| FKTN | Fukutin | C | 82.25 | 0.00 | −0.64 | ++ | Yes | NA | LGMD-2M (may present as DCM) |
| SDHA | Succinate dehydrogenase flavoprotein subunit | D | 10.95 | 0.00 | 2.32 | ++ | Yes | NA | Leigh syndrome (rarely associated with pediatric recessive DCM) |
| DTNA | α-dystrobrevin | D | 21.65 | 0.92 | 1.17 | + | NA | No | LVNC, CHD |
| LAMA2 | Laminin subunit α-2 | D | 79.64 | 0.00 | −1.58 | + | NA | NA | Merosin-deficient congenital MD/LGMD (rarely includes DCM) |
| SYNM | Synemin | D | NA | 0.00 | −0.15 | NA | NA | NA | Accumulates in skeletal myopathy |
Genetic evidence: +++ co-segregation of variants in multiple (3+) families, with at least one family showing variant co-segregation in 5 or more affected individuals; ++ co-segregation of variant in 1 or more small families (<5 affected); + variant demonstrated in single cases (with/without positive family history), or SNPs associated with DCM susceptibility.
Animal models: +++ Spontaneous development of DCM in animal model with a heterozygous gene loss-of-function or expressing a human disease-associated non-synonymous variant; ++ spontaneous DCM present in homozygous gene loss-of-function model, or stress-induced DCM in model of a human non-synonymous variant; + No DCM but other relevant phenotypes, eg. isolated ventricular dilation or contractile dysfunction, evidence of reduced contractile reserve, skeletal myopathy. See Supplemental Table X for more details.
α-MHC is major myosin isoform in murine ventricle: human MYH7 mutations modelled in murine myh6 gene.
AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; BMD, Becker muscular dystrophy; BS, Brugada syndrome; CD, conduction-system defects; CHD, congenital heart disease; CM, congenital myopathy; CNM, centronuclear myopathy; DCM, dilated cardiomyopathy; DM, distal myopathy; DMD, Duchenne muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; EFE, endomyocardial fibroelastosis; HCK, high creatine kinase; HCM, hypertrophic cardiomyopathy; HMERF, hereditary myopathy with early respiratory failure; LGMD, limb girdle muscular dystrophy; LQTS, long QT syndrome; LVH, left ventricular hypertrophy; LVNC, left ventricular non-compaction; MD, muscular dystrophy; MM, myofibrillar myopathy; MSM, myosin storage myopathy; NA, not available; NSS, neurogenic scapuloperoneal syndrome; RCM, restrictive cardiomyopathy; RMD, rippling muscle disease; SIDS, sudden infant death syndrome; SPM, scapuloperoneal myopathy; SSS, sick sinus syndrome; TMD, tibial muscular dystrophy; VF, ventricular fibrillation.