Table 1. Disease Validity Classifications for DCM Genes Considered Within a Monogenic Framework.
The 51 genes curated for DCM by the ClinGen DCM Gene Curation Panel are grouped by levels of evidence supporting a Mendelian relationship with the DCM phenotype.5 Genes meeting a classification of moderate, strong, or definitive, as defined by the ClinGen framework, have high levels of evidence that can be used for molecular diagnosis of DCM in the clinical setting. Genes with limited classifications have variable degrees of evidence, some of which may emerge as high evidence genes in the future. Genes in the minimal evidence category, assigned a “disputed” or “no known disease relationship” classification, are unlikely to accumulate evidence to reach a high classification standard. However, while highly unlikely to be a monogenic cause of DCM, it is possible that genes in this category may have a modest clinical effect as a genetic modifier of disease. Abbreviations: AD, autosomal dominant; AR; autosomal recessive; DCM, dilated cardiomyopathy; MOI, mode of inheritance; SD, semi-dominant (both AD and AR mechanisms reported).
| ClinGen DCM Gene-Disease Validity Classification | Gene | Protein | MOI | Function | |
|---|---|---|---|---|---|
| High Evidence Genes | Moderate | ACTC1 | Actin, alpha cardiac 1 | AD | Sarcomere |
| Moderate | ACTN2 | Alpha actinin 2 | AD | Sarcomere | |
| Definitive | BAG3 | BCL2-associated anthanogene 3 | AD | Co-chaperone/ Heat shock protein |
|
| Definitive | DES | Desmin | AD | Cytoskeleton | |
| Strong | DSP | Desmoplakin | AD | Desmosome | |
| Definitive | FLNC | Filamin C | AD | Sarcomere | |
| Moderate | JPH2 | Junctophilin 2 | SD | Junctional membrane | |
| Definitive | LMNA | Lamin A/C | AD | Nuclear envelope | |
| Definitive | MYH7 | Myosin heavy chain 7, beta | AD | Sarcomere | |
| Moderate | NEXN | Nexilin | AD | Cytoskeleton | |
| Definitive | PLN | Phospholamban | AD | Sarcoplasmic reticulum | |
| Definitive | RBM20 | RNA binding motif protein 20 | AD | Nucleus/RNA-binding | |
| Definitive | SCN5A | Sodium channel, voltage-gated type V, alpha | AD | Ion channel | |
| Definitive | TNNC1 | Troponin C, slow | AD | Sarcomere | |
| Moderate | TNNI3 | Troponin I | AD | Sarcomere | |
| Definitive | TNNT2 | Troponin T | AD | Sarcomere | |
| Moderate | TPM1 | Tropomyosin 1 | AD | Sarcomere | |
| Definitive | TTN | Titin | AD | Sarcomere | |
| Moderate | VCL | Metavinculin | AD | Cytoskeleton | |
| Low/ Variable Evidence Genes | Limited | ABCC9 | ATP-binding cassette, subfamily C, member 9 | AD | Ion channel, sarcomere |
| Limited | ANKRD1 | Ankyrin repeat domain 1 | AD | Sarcomere | |
| Limited | CSRP3 | Cysteine-rich protein 3 | AD | Cytoskeleton | |
| Limited | CTF1 | Cardiotrophin 1 | AD | Cytokine | |
| Limited | DSG2 | Desmoglein 2 | AD | Desmosome | |
| Limited | DTNA | Dystrobrevin, Alpha | AD | Sarcomere | |
| Limited | EYA4 | Eyes absent 4 | AD | Nucleus | |
| Limited | GATAD1 | GATA zinc finger domain-containing protein 1 | AR | Nucleus | |
| Limited | ILK | Integrin-linked kinase | AD | Cytoskeleton | |
| Limited | LAMA4 | Laminin, alpha 4 | AD | Extracellular matrix | |
| Limited | LDB3 | LIM domain binding 3 | AD | Cytoskeleton | |
| Limited | MYBPC3 | Myosin-binding protein C | AD | Sarcomere | |
| Limited | MYH6 | Myosin heavy chain 6, alpha | AD | Sarcomere | |
| Limited | MYL2 | Myosin light chain 2 | AD | Sarcomere | |
| Limited | MYPN | Myopalladin | AD | Sarcomere | |
| Limited | NEBL | Nebulette | AD | Sarcomere | |
| Limited | NKX2–5 | NL2 homeobox 5 | AD | Nucleus | |
| Limited | OBSCN | Obscurin | AD | Sarcomere | |
| Limited | PLEKHM2 | Pleckstrin homology domain-containing protein, family M, member 2 | AR | Cytoskeleton | |
| Limited | PRDM16 | PR domain-containing protein 16 | AD | Nucleus | |
| Limited | PSEN2 | Presenilin 2 | AD | Plasma membrane | |
| Limited | SGCD | Sarcoglycan, delta | AD | Cytoskeleton | |
| Limited | TBX20 | T-box 20 | AD | Nucleus | |
| Limited | TCAP | Telethonin | AD | Sarcomere | |
| Limited | TNNI3K | TNNI3-interacting kinase | AD | Sarcomere | |
| Minimal Evidence Genes | No known disease relationship | LRRC10 | Leucine-rich repeat-containing protein 10 | AR | Cytoskeleton |
| No known disease relationship | MIB1 | Mindbomb E3 ubiquitin protein ligase 1 | AD | Cytoskeleton | |
| Disputed | MYL3 | Myosin light chain 3 | AD | Cytoskeleton | |
| No known disease relationship | NPPA | Natriuretic peptide precursor A | AR | Hormone | |
| Disputed | PDLIM3 | PDZ and LIM domain protein 3 | AD | Cytoskeleton | |
| Disputed | PKP2 | Plakophilin 2 | AD | Desmosome | |
| Disputed | PSEN1 | Presenilin 1 | AD | Plasma membrane |