Table 2.
Gene | Ranking | Number of variants | Type of mutations | Protein | Protein location/function | Expression | Animal studies | Gene tolerance | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Sarcomere | Z‐disk | Heart | Skeletal muscle | pLi | Z‐score | ||||||
PDLIM5 | 25 | 9 | 5 | 2/5 LoF | PDZ and LIM domain protein 5 | Z‐disk | High | High | KO mouse: DCM | 0.01 | −0.47 |
MYOM1 | 16 | 37 | 8 | All missense | Myomesin‐1 | Sarcomere | High | High | — | 0 | −0.35 |
CKM | 28 | 31 | 4 | 2/4 LoF | Creatine kinase, muscle | Cytoplasm | Medium | High | — | 0.01 | 0.95 |
CMYA5 | 30 | 23 | 14 | 1/14 LoF | Cardiomyopathy associated protein 5 | Anchor protein for PKA | Medium | High | — | 0 | −2.73 |
PDE4DIP | 32 | 33 | 27 | 1/27 LoF | Phosphodiesterase 4D interacting protein | Anchor protein for cAMP‐dependent pathway | Medium | High | — | — | — |
TXLNB | 33 | 16 | 5 | All missense | Beta‐taxilin | Promotes motor nerve regeneration | Medium | High | — | 0 | −0.91 |
MYLK3 | 43 | 92 | 5 | All missense | Myosin light chain kinase 3 | Kinase that phosphorolates MYL2 | High | Medium | KO mouse: DCM | 0.14 | −0.25 |
LMOD3 | 48 | 26 | 6 | All missense | Leiomodin‐3 | Sarcomere | Low | Low | Only for LMOD2: DCM | 0.01 | −2.05 |
MYOM2 | 55 | 75 | 16 | All missense | Myomesin‐2 | Sarcomere | High | High | — | 0 | −5.87 |
MYH11 | 72 | 190 | 7 | All missense | Myosin‐11 | Sarcomere | Absent | Absent | KO mouse: no cardiac phenotype | 1 | 3.15 |
XIRP1 | 73 | 89 | 10 | All missense | Xin actin binding repeat containing 1 | Sarcomere | Low | Low | KO mouse: myopathy | 0 | −1.7 |
DMPK | 75 | 131 | 6 | All missense | Dystrophia myotonica protein kinase | Kinase necessary maintaining muscle structure | Medium | Medium | KO mouse: decreased contractility | 0.03 | 1.47 |
ADCK3 | 84 | 74 | 4 | 1/4 LoF | aarF domain containing kinase 3 | Mitochondrial respiratory chain | Low | High | — | 0 | −1.6 |
SORBS1 | 87 | 143 | 7 | All missense | Sorbin and SH3 domain containing 1 | Involved in cytoskeletal formation | Low | Low | — | 0 | 0.3 |
TNXB | 92 | 469 | 34 | 1/34 LoF | Tenascin XB | Extracellular matrix | Low | Low | — | 0.77 | 3 |
ALPK3 | 92 | 51 | 12 | All missense | Alpha kinase 3 | Cardiomyocyte differentiation | Medium | High | — | 0 | 0.31 |
OBSCN | 105 | 395 | 200 | 4/200 LoF | Obscurin | Z‐disk | Medium | High | — | −1 | 0 |
SORBS2 | 109 | 795 | 4 | All missense | Sorbin and SH3 domain containing 2 | Involved in cytoskeletal formation | Medium | Low | — | 0.09 | 0.38 |
SPEG | 111 | 355 | 22 | All missense | Striated muscle enriched protein kinase | Myocyte cytoskeletal development | Low | Medium | KO mouse: HF | 1 | 6 |
SYNM | 116 | 84 | 14 | All missense | Synemin | Intermediate filament within the cytoskelet | Low | Medium | KO mouse: HF | 0 | −0.15 |
XIRP2 | 117 | 128 | 20 | 4/20 LoF | Xin actin binding repeat containing 2 | Sarcomere | Low | High | — | 0 | −5 |
Abbreviations: DCM, dilated cardiomyopathy; KO, knockout; LoF, loss of function; PKA, protein kinase A.