Extended Data Table 2.
Summary of genes associated with recessive CM without replication in multiple families/studies
| Gene | Gene function | CM | PMID | Cases | Variant(s) | Methods |
|---|---|---|---|---|---|---|
| AASDH | Synthesises peptides independently of ribosomes | DCM | 32870709 | 1 | p.Tyr1061Cysfs*3 (last exon) | ES/HM |
| ACACB | Fatty acid synthesis enzyme | LVNC | 32870709 | 1 | p.Arg2102Gln | ES/HM |
| Supporting evidence: KO mice had normal lifespan, higher fatty acid oxidation rate, lower fat (PMID:11283375). | ||||||
| BICD2 | Cargo adaptor protein for retrograde COPI-independent Golgi-ER transport | DCM | 36068540 | 3 | p.Arg810His | ES |
| Supporting evidence: KO zebrafish displayed a greater rate of embryonic lethality; echocardiography showed a reduction in cardiac output but no significant change in cardiac area or volume, unlike DCM. RNAseq of the zebrafish showed an altered transcriptome, relative to wild-type, though the findings were not particularly specific to DCM (PMID:36068540). | ||||||
| CASZ1 | Zinc finger transcription factor | DCM/LVNC | 32870709 | 1 | p.Ser237Cys | ES/HM |
| Supporting evidence: KO mice: embryonic lethality, abnormal heart development/shape, Z line formation (PMID:25190801). GWAS loci - atrial fibrillation (PMID:35872910,30061737,29892015), ECG traits (PMID:36050321,32916098). | ||||||
| GATAD1 | H3K4me3 histone code reader protein | DCM | 21965549 | 3 | p.Ser102Pro | Linkage /HM/ES |
| Supporting evidence: In KO zebrafish, 1/6 had enlarged heart, all had lower survival rates (PMID:28955713). | ||||||
| GET3 (ASNA1) | Chaperone for the insertion of tail-anchored proteins into the ER membrane | DCM | 31461301 | 2 | p.Cys289Trp / p.Gln305* / p.Val163Ala | ES |
| Supporting evidence: Homozygous KO zebrafish died by 9 days post fertilisation. Injections of wild-type GET3/ASNA1 mRNA slowed the progression of cardiac failure whereas mutant GET3/ASNA1 mRNA did not (PMID:31461301). | ||||||
| KIF20A | Kinesin motor protein for Aurora B and Golgi vesicle trafficking | RCM | 29357359 | 2 | p.Arg182Trp / p.Ser635Thrfs*15 | ES |
| Supporting evidence: 90% of KIF20A morpholino-knockdown zebrafish developed cardiac oedema, pooling of red blood cells proximal to the atrium, tachycardia and increased fractional shortening by 6 days post fertilisation. Wild-type KIF20A cDNA partially rescued the phenotype, whereas mutant cDNA did not. Histology of the fish showed increased ventricular thickness in the mutants (PMID:29357359). KIF20A homozygous KO mice die by 3-4 weeks of age (PMID:27626380). | ||||||
| PHACTR2 | Phosphatase and actin regulator | DCM/LVNC | 36674904 | 1 | p.Arg511His | ES |
| RHBDF1 | Inactive intramembrane rhomboid protein that regulates EGFR signalling | DCM | 32870709 | 3 | p.Gly665Trp / p.Phe405Serfs*16 | ES/HM |
| SLC6A6 | Taurine transporter | DCM | 31903486 | 2 | p.Gly399Val | ES/HM |
| Supporting evidence: KO mice had cardiac dysfunction and fractional shortening at older age (PMID:20804595). Putative causal gene at a DCM GWAS locus (PMID:33677556). | ||||||
| SOD2 | Manganese-superoxide dismutase | DCM | 31494578 | 1 | p.Gly181Val | ES |
| Supporting evidence: KO mice can develop DCM and demonstrate early death (PMID:7493016,8790408). Putative causal gene at a myocardial fibrosis (interventricular septum and LV free wall) GWAS locus (PMID:37081215). | ||||||
| TAF1A | Part of a transcription factor for ribosomal DNA | DCM | 28472305 | 2 | p.Leu84Ser / p.Gly341Arg | ES |
| Supporting evidence: ClinVar: compound het p.Gly341Arg and p.Thr261Pro in Jamaican African-descent female 0-9 years with RCM (SCV001775486.1). A zebrafish TAF1A KO model showed a heart failure like phenotype; early lethality (death by 11 days post fertilisation); pericardial oedema; reduction in ventricular fractional shortening (PMID:28472305). | ||||||
| ULK1 | Autophagosome formation | DCM | 32870709 | 1 | p.Arg691Trp | ES/HM |
| Supporting evidence: Double ULK1/ULK2 KO perinatal mice develop cardiomyopathy (PMID:34724805,35018428,35104184). | ||||||
DCM, dilated cardiomyopathy; ECG, electrocardiogram; ES, exome sequencing; GWAS, genome-wide association study; HM, homozygosity mapping; Linkage, linkage analysis; KO, knockout; LVNC, left ventricular non-compaction; RCM, restrictive cardiomyopathy.