Table 1.
Summary of 18 genes associated with autosomal recessive CM with robust evidence
| Gene | Gene function | Phenotype | Reports | Families | Biallelic cases | Variant classes | Evidence summary | GWAS associations | Mouse knockout phenotypes |
|---|---|---|---|---|---|---|---|---|---|
| ALPK3 | Localization of myomesin (M-band and nucleus) | DCM/HCM | 9 (refs. 11,52–59) | 17 | 26 | PTV/missense | Exome (8 trio, 5 proband). Panel (2 trio, 2 proband). Max LOD = 2.9 (ref. 52) | HCM, LV/ECG traits | HCM and DCM features |
| BAG5 | Co-chaperone of proteostasis regulation | DCM | 2 (refs. 60,61) | 5 | 6 | PTV | Exome (3 trio, 2 proband) | – | LV dilation and arrhythmogenicity |
| CAP2 | Thin filament protein (actin regulation) | DCM | 3 (refs. 62–64) | 3 | 4 | PTV | Exome (2 trio, 1 proband). Max LOD = 1.9 (ref. 62) | – | Severe DCM, conduction anomalies, sudden death |
| FBXO32 | E3 ubiquitin ligase subunit | DCM | 2 (refs. 65,66) | 2 | 6 | Missense | Exome (2 trio). Max LOD = 3.4 (ref. 65) | HCM, AF, ECG traits | – |
| FLII | Actin remodeling protein | DCM | 2 (refs.10,67) | 3 | 3 | PTV/missense | Exome (3 trio) | – | Embryonic lethality |
| JPH2 | Junctional membrane complex | DCM | 6 (refs. 7,8,10,68–70) | 7 | 7 | PTV/missense | Exome (2 trio, 2 proband). Panel (1 trio, 2 proband) | – | Embryonic lethality |
| KLHL24 | E3 ubiquitin ligase substrate adapter | HCM | 3 (refs. 10,71,72) | 4 | 9 | PTV/missense | Exome (3 trio, 1 proband). Max LOD = 3.6 (ref. 71) | – | – |
| LDB3 | Z-disc protein | DCM | 1 (ref. 73) | 5 | 5 | PTV | Exome (5 trio) | ECG traits | Severe DCM, early death |
| LEMD2 | Inner nuclear membrane protein | ACM | 1 (ref. 74) | 2 | 11 | Missense | Exome (2 large pedigrees). Max LOD = 7.3 (estimated)74 | – | DCM-like phenotype with fibrosis and arrhythmia (p.Leu13Arg knock-in) |
| LMOD2 | Thin filament protein (actin elongation) | DCM | 5 (refs. 75–79) | 5 | 6 | PTV | Exome (4 trio). Panel (1 trio) | – | DCM-like phenotype, early death |
| MYZAP | Intercalated disc protein | DCM | 2 (refs. 80,81) | 3 | 8 | PTV | Exome (3 trio) | AF | TAC-induced hypertrophy, HF, increased mortality |
| NRAP | Intercalated disc protein | DCM | 10 (refs. 7,10,19,61,72,82–86) | 30 | 32 | PTV/missense |
Exome (7 trio, 12 proband). Panel (2 trio, 9 proband). RVAS: 1.9% versus 0% (P < 0.00001)19 |
ECG traits | – |
| PLEKHM2 | Kinesin transport cargo adapter protein | DCM | 2 (refs. 87,88) | 2 | 5 | PTV | Exome (1 trio). Panel (1 trio). Max LOD = 2.8 (estimated)87 | LV traits | – |
| PPA2 | Inorganic pyrophosphatase | DCM/SCD | 7 (refs. 7,8,89–93) | 32 | 53 | Missense | Exome (21 trio, 3 proband). Panel (8 trio) | – | – |
| PPP1R13L | NF-κB and p53 inhibitor | DCM | 6 (refs. 9,10,94–97) | 11 | 15 | PTV/missense | Exome (6 trio, 5 proband) | – | Severe and rapidly progressing DCM |
| RPL3L | Muscle-specific ribosomal protein | DCM | 4 (refs. 10,98–100) | 6 | 9 | Missense | Exome (6 trio) | AF | – |
| SLC30A5 | Zinc transporter | CM | 1 (ref. 101) | 2 | 4 | PTV | Exome (2 trio) | – | Sudden death (60%) |
| TRIM63 | E3 ubiquitin ligase | HCM | 6 (refs. 25,102–106) | 28 | 32 | PTV/missense |
Panel (7 trio, 21 proband). RVAS: 0.4% versus 0% (P = 0.0002)104, 2.1% versus 0% (P = 0.003)25 |
Strain, ECG traits | Severe hypertrophy (TAC or TRIM55 double-knockout) |
For the evidence summary, cases are summarized as ‘exome’ (variants detected with genome-wide methods of genome and exome sequencing) or ‘panel’ (sequencing of distinct sets of CM-associated genes only), and as ‘trio’ (confirmed recessive inheritance with heterozygous parents) or ‘proband’ (recessive inheritance not confirmed but likely). The summary also includes the maximum reported or estimated LOD scores for large family pedigrees and details of the RVAS enrichment analysis. See the Supplementary Text and Methods for further details and citations for this genetic evidence, GWAS associations and mouse knockout phenotypes. Strain, myocardial strain in longitudinal direction; TAC, transverse aortic constriction.