Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review
Abstract
:1. Introduction
1.1. Identification of Reported Minor CMP Genes
1.2. Gathering Sources
1.3. Literature Review
2. Gene Classification
2.1. Definitive Genes Associated with ACM, DCM, and HCM
2.2. Minor Genes in ACM, DCM, and HCM
2.2.1. ABCC9
2.2.2. ACTN2
2.2.3. ANKRD1
2.2.4. CALR3
2.2.5. CDH2
2.2.6. CSRP3
2.2.7. CTF1
2.2.8. CTNNA3
2.2.9. DTNA
2.2.10. EYA4
2.2.11. GATAD1
2.2.12. ILK
2.2.13. JPH2
2.2.14. KLF10
2.2.15. KLHL24
2.2.16. LAMA4
2.2.17. LDB3
2.2.18. MT-TI
2.2.19. MYH6
2.2.20. MYLK2
2.2.21. MYOM1
2.2.22. MYOZ2
2.2.23. MYPN
2.2.24. NEBL
2.2.25. NEXN
2.2.26. NKX2-5
2.2.27. OBSCN
2.2.28. PDLIM3
2.2.29. PLEKHM2
2.2.30. PRDM16
2.2.31. PSEN2
2.2.32. RPS6KB1
2.2.33. RYR2
2.2.34. SGCD
2.2.35. TBX20
2.2.36. TCAP
2.2.37. TGFB3
2.2.38. TJP1
2.2.39. TNNI3K
2.2.40. TRIM63
2.2.41. VCL
3. Gene–Disease Validity and Clinical Evidence
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Location (GRCh38) | Hereditary | Definitive Phenotype Association [45] | N. P/LP Variants | N. VUS | Other Phenotype Associations | |||
---|---|---|---|---|---|---|---|---|---|
ClinGen [45] | GeneReviews [42] | EMQN [43,44] | Expert Consensus Statement [53] | ||||||
ACTC1 | 15q14 | AD | HCM | 8 | 290 | DCM (moderate) | DCM (moderate) | DCM (moderate) | DCM (moderate) |
BAG3 | 10q26.11 | AD | DCM | 101 | 513 | - | - | - | - |
DES | 2q35 | AD | DCM | 16 | 58 | ACM (moderate) | ACM (moderate) | ACM (moderate) | - |
DSC2 | 18q12.1 | AD, AR | ACM (ARVC, less frequent ALVC/BiVACM) | 57 | 667 | DCM (moderate) | - | - | - |
DSG2 | 18q12.1 | AD | ACM (ARVC, ALVC, BiVACM) | 85 | 753 | DCM (limited) | DCM (limited) | - | - |
DSP | 6p24.3 | AD | ACM (ALVC/BiVACM, occasional hair/skin features) | 472 | 1430 | - | DCM (definitive) | DCM (definitive) | DCM (definitive) |
FHOD3 | 18q12.2 | - | HCM | 4 | 24 | - | - | - | - |
FLNC | 7q32.1 | AD | DCM | 359 | 1697 | - | - | ACM (limited) | - |
LMNA | 1q22 | AD | DCM | 86 | 229 | ACM (limited) | - | - | - |
MYBPC3 | 11p11.2 | AD | HCM | 706 | 1228 | ACM; DCM (limited) | DCM (limited) | - | - |
MYH7 | 14q11.2 | AD | DCM; HCM | 291 | 1642 | ACM (limited) | - | - | - |
MYL2 | 12q24.11 | AD | HCM | 12 | 206 | DCM (limited) | DCM (limited) | - | - |
MYL3 | 3p21.31 | AD, AR | HCM | 3 | 197 | ACM (limited) | - | - | - |
PKP2 | 12p11.21 | AD | ACM (ARVC, less frequent ALVC/BiVACM) | 271 | 701 | - | - | - | - |
RBM20 | 10q25.2 | AD | DCM | 16 | 676 | HCM (limited) | - | - | - |
SCN5A | 3p22.2 | AD | DCM | 19 | 252 | ACM (limited) | - | - | - |
TMEM43 | 3p25.1 | AD | ACM (ARVC, BiVACM) | 2 | 378 | - | - | - | - |
TNNC1 | 3p21.1 | AD | DCM | 7 | 139 | HCM (definitive) | HCM (moderate) | HCM (moderate) | HCM (moderate) |
TNNI3 | 19q13.42 | AD | HCM | 41 | 247 | DCM (moderate) | DCM (moderate) | DCM (moderate) | DCM (moderate) |
TNNT2 | 1q32.1 | AD | DCM; HCM | 53 | 281 | - | - | - | - |
TPM1 | 15q22.2 | AD | HCM | 24 | 267 | DCM (moderate) | DCM (moderate) | DCM (moderate) | DCM (moderate) |
TTN | 2q31.2 | AD | DCM | 2381 | 5144 | ACM; HCM (limited) | HCM (limited) | - | - |
ClinGen [45] | GeneReviews [42] | EMQN [43,44] | Expert Consensus Statement [53] | ClinGen [45] | GeneReviews [42] | EMQN [43,44] | Expert Consensus Statement [53] | ClinGen [45] | GeneReviews [42] | EMQN [43,44] | Expert Consensus Statement [53] | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Gene | Location (GRCh38) | Hereditary | ACM | DCM | HCM | |||||||||
ABCC9 | 12p12.1 | AD | not associated | not associated | - | not associated | limited | limited | - | not associated | not associated | not associated | - | not associated |
ACTN2 | 1q43 | AD | not associated | not associated | not associated | not associated | not associated | moderate | moderate | moderate | not associated | moderate | not associated | moderate |
ANKRD1 | 10q23.31 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | limited | - | - |
CALR3 | 19p13.11 | AD | not associated | not associated | - | - | not associated | not associated | - | - | not associated | limited | - | - |
CDH2 | 18q12.1 | AD | limited | not associated | - | not associated | not associated | not associated | - | not associated | not associated | not associated | - | not associated |
CSRP3 | 11p15.1 | AD, SD | not associated | not associated | - | not associated | limited | limited | - | not associated | moderate | moderate | - | moderate |
CTF1 | 16p11.2 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
CTNNA3 | 10q21.3 | AD | limited | not associated | - | not associated | not associated | not associated | - | not associated | not associated | not associated | - | moderate |
DTNA | 18q12.1 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
EYA4 | 6q23.2 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
GATAD1 | 7q21.2 | AR | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
ILK | 11p15.4 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
JPH2 | 20q13.12 | AD, SD | not associated | not associated | not associated | not associated | moderate | moderate | moderate | moderate | moderate | moderate | not associated | moderate |
KLF10 | 8q22.3 | AD | not associated | not associated | - | - | not associated | not associated | - | - | limited | limited | - | - |
KLHL24 | 3q27.1 | AR | not associated | - | - | - | not associated | - | - | - | moderate | - | - | - |
LAMA4 | 6q21 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
LDB3 | 10q23.2 | AD | not associated | not associated | - | not associated | limited | limited | - | not associated | not associated | not associated | - | not associated |
MT-TI | - | - | not associated | - | - | - | not associated | - | - | - | moderate | - | - | - |
MYH6 | 14q11.2 | AD | not associated | not associated | - | - | limited | limited | - | - | limited | limited | - | - |
MYLK2 | 20q11.21 | AD | not associated | not associated | - | - | not associated | not associated | - | - | not associated | limited | - | - |
MYOM1 | 18p11.31 | AD | not associated | not associated | - | - | not associated | not associated | - | - | not associated | limited | - | - |
MYOZ2 | 4q26 | AD | not associated | not associated | - | - | not associated | not associated | - | - | not associated | limited | - | - |
MYPN | 10q21.3 | AD | not associated | not associated | - | - | not associated | limited | - | - | not associated | limited | - | - |
NEBL | 10p12.31 | AD | not associated | not associated | - | - | limited | limited | - | -- | not associated | not associated | - | - |
NEXN | 1p31.1 | AD | not associated | not associated | - | - | moderate | moderate | - | - | limited | limited | - | - |
NKX2-5 | 5q35.1 | AD | not associated | not associated | - | - | limited | limited | - | not associated | not associated | - | - | |
OBSCN | 1q42.13 | AD | not associated | not associated | - | limited | limited | - | - | limited | not associated | - | - | |
PDLIM3 | 4q35.1 | AD | not associated | not associated | - | - | not associated | not associated | - | - | limited | limited | - | - |
PLEKHM2 | 1p36.21 | AR | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
PRDM16 | 1p36.32 | AD | not associated | not associated | - | limited | limited | - | - | not associated | not associated | - | - | |
PSEN2 | 1q42.13 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
RPS6KB1 | 17q23.1 | AD | not associated | not associated | - | - | not associated | not associated | - | - | limited | not associated | - | - |
RYR2 | 1q43 | AD | not associated | not associated | - | - | not associated | not associated | - | - | limited | limited | - | - |
SGCD | 5q33.2-q33.3 | AD | not associated | not associated | - | - | limited | limited | - | not associated | not associated | - | - | |
TBX20 | 7p14.2 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | not associated | - | - |
TCAP | 17q12 | AD | not associated | not associated | - | - | limited | limited | - | - | not associated | limited | - | - |
TGFB3 | 14q24.3 | AD | limited | not associated | - | - | not associated | not associated | - | - | not associated | not associated | - | - |
TJP1 | 15q13.1 | AD | limited | not associated | - | - | not associated | not associated | - | - | not associated | not associated | - | - |
TNNI3K | 1p31.1 | AD | not associated | not associated | - | limited | limited | - | - | not associated | not associated | - | - | |
TRIM63 | 1p36.11 | AD, AR | not associated | not associated | - | - | not associated | not associated | - | - | moderate | limited | - | - |
VCL | 10q22.2 | AD | not associated | not associated | - | - | moderate | moderate | - | - | not associated | limited | - | - |
Gene | Hereditary | Protein | ACM | DCM | HCM | N. P/LP Variants | N. VUS | Phenotype Submission | Animal Studies |
---|---|---|---|---|---|---|---|---|---|
ABCC9 | AD | ATP-binding cassette subfamily C member 9 | not associated | limited | not associated | 9 | 712 | DCM | not available |
ACTN2 | AD | Alpha-actinin 2 | not associated | not associated | not associated | 8 | 685 | DCM, HCM | not available |
ANKRD1 | AD | Ankyrin repeat domain 1 | not associated | limited | not associated | 0 | 227 | DCM, HCM | [73] |
CALR3 | AD | Calreticulin 3 | not associated | not associated | not associated | 0 | 145 | HCM | [77,78] |
CDH2 | AD | Cadherin 2 | limited | not associated | not associated | 3 | 10 | ACM | not available |
CSRP3 | AD, SD | Cysteine- and glycine-rich Protein 3 | not associated | limited | moderate | 16 | 233 | DCM, HCM | [90] |
CTF1 | AD | Cardiotrophin 1 | not associated | limited | not associated | 0 | 3 | HCM | not available |
CTNNA3 | AD | Catenin alpha 3 | limited | not associated | not associated | 3 | 400 | ACM | [99] |
DTNA | AD | Dystrobrevin alpha | not associated | limited | not associated | 1 | 7 | DCM | not available |
EYA4 | AD | EYA transcriptional coactivator and phosphatase 4 | not associated | limited | not associated | 26 | 445 | DCM | [103] |
GATAD1 | AR | GATA zinc finger domain-containing 1 | not associated | limited | not associated | 1 | 75 | DCM | [108] |
ILK | AD | Integrin-linked kinase | not associated | limited | not associated | 0 | 6 | DCM | [112] |
JPH2 | AD, SD | Junctophilin 2 | not associated | moderate | moderate | 5 | 337 | DCM, HCM | [120] |
KLF10 | AD | Krüppel-like factor 1 | not associated | not associated | limited | 0 | 1 | HCM | not available |
KLHL24 | AR | Kelch-like family member 24 | not associated | not associated | moderate | 3 | 1 | HCM | [124] |
LAMA4 | AD | Laminin subunit alpha 4 | not associated | limited | not associated | 0 | 704 | DCM | [110] |
LDB3 | AD | LIM domain-binding 3 | not associated | limited | not associated | 3 | 141 | DCM | [138] |
MT-TI | - | Transfer RNA, mitochondrial, isoleucine | not associated | not associated | moderate | 6 | 11 | HCM | not available |
MYH6 | AD | Myosin heavy chain 6 | not associated | limited | limited | 7 | 983 | DCM, HCM | [149] |
MYLK2 | AD | Myosin light chain kinase 2 | not associated | not associated | not associated | 0 | 242 | HCM | not available |
MYOM1 | AD | Myomesin 1 | not associated | not associated | not associated | 0 | 738 | HCM | not available |
MYOZ2 | AD | Myozenin 2 | not associated | not associated | not associated | 1 | 98 | HCM | [160,162] |
MYPN | AD | Myopalladin | not associated | not associated | not associated | 31 | 646 | DCM, HCM | [166] |
NEBL | AD | Nebulette | not associated | limited | not associated | 1 | 474 | DCM | [274] |
NEXN | AD | Nexilin F-actin-binding protein | not associated | moderate | limited | 20 | 260 | DCM, HCM | [175,178] |
NKX2-5 | AD | NK2 homeobox 5 | not associated | limited | not associated | 1 | 3 | DCM | not available |
OBSCN | AD | Obscurin | not associated | limited | limited | 0 | 1 | DCM, HCM | [193,194,195,196] |
PDLIM3 | AD | PDZ and LIM domain 3 | not associated | not associated | limited | 0 | 192 | HCM | not available |
PLEKHM2 | AR | Pleckstrin homology and RUN domain-containing M2 | not associated | limited | not associated | 0 | 378 | DCM | not available |
PRDM16 | AD | PR/SET domain 16 | not associated | limited | not associated | 1 | 30 | DCM | [207,210] |
PSEN2 | AD | Presenilin 2 | not associated | limited | not associated | 0 | 48 | DCM | [213] |
RPS6KB1 | AD | Ribosomal protein S6 kinase B1 | not associated | not associated | limited | 0 | 0 | HCM | not available |
RYR2 | AD | Ryanodine receptor 2 | not associated | not associated | limited | 0 | 72 | HCM | [218,223] |
SGCD | AD | Sarcoglycan delta | not associated | limited | not associated | 17 | 132 | DCM | not available |
TBX20 | AD | T-box transcription factor 20 | not associated | limited | not associated | 4 | 9 | DCM | [231,233,234] |
TCAP | AD | Titin-cap | not associated | limited | not associated | 20 | 162 | DCM, HCM | not available |
TGFB3 | AD | Transforming growth factor beta 3 | limited | not associated | not associated | 4 | 44 | ACM | not available |
TJP1 | AD | Tight junction protein 1 | limited | not associated | not associated | 0 | 0 | ACM | not available |
TNNI3K | AD | TNNI3 interacting kinase | not associated | limited | not associated | 5 | 44 | DCM | not available |
TRIM63 | AD, AR | Tripartite motif-containing 63 | not associated | not associated | moderate | 1 | 11 | HCM | [36,259] |
VCL | AD | Vinculin | not associated | moderate | not associated | 3 | 664 | DCM, HCM | [266,268,269,270,272] |
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Micolonghi, C.; Perrone, F.; Fabiani, M.; Caroselli, S.; Savio, C.; Pizzuti, A.; Germani, A.; Visco, V.; Petrucci, S.; Rubattu, S.; et al. Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review. Int. J. Mol. Sci. 2024, 25, 9787. https://doi.org/10.3390/ijms25189787
Micolonghi C, Perrone F, Fabiani M, Caroselli S, Savio C, Pizzuti A, Germani A, Visco V, Petrucci S, Rubattu S, et al. Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review. International Journal of Molecular Sciences. 2024; 25(18):9787. https://doi.org/10.3390/ijms25189787
Chicago/Turabian StyleMicolonghi, Caterina, Federica Perrone, Marco Fabiani, Silvia Caroselli, Camilla Savio, Antonio Pizzuti, Aldo Germani, Vincenzo Visco, Simona Petrucci, Speranza Rubattu, and et al. 2024. "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review" International Journal of Molecular Sciences 25, no. 18: 9787. https://doi.org/10.3390/ijms25189787