Table 2 Fam1 and Fam2 genes and corresponding variants that overlap with the ACM genes or the PKP2-related genes
From: Exploring digenic inheritance in arrhythmogenic cardiomyopathy
Family | Gene seta | Gene rankb | Gene name | HGVSp | Variant consequence | PROVEAN predictionc | Population frequencyd | Genotypee | Comment |
|---|---|---|---|---|---|---|---|---|---|
Fam2 | ACM | – | TTN | ENSP00000434586.1:p.Gln24857His | missense | deleterious | rare | het in Fam2.II.1 and Fam2.I.1 | Mutations in TTN can cause ACM [8]. |
Fam2 | ACM | – | TTN | ENSP00000434586.1:p.Arg23483His | missense | deleterious | rare | het in Fam2.II.1 and Fam2.I.1 | Mutations in TTN can cause ACM [8]. |
Fam2 | ACM | – | TTN | ENSP00000434586.1:p.Ile3716Val | missense | neutral | common | het in Fam2.II.1 and Fam2.I.1 | Mutations in TTN can cause ACM [8]. |
Fam1 | PKP2 (GO: neg. Reg. cell prolif.) | 1 | DAG1 | ENSP00000312435.2:p.Leu86Phe | missense | neutral | rare | het in Fam1.III.2, Fam1.III.3, Fam1.II.1 | β-dystroglycan binds to Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice [42]. |
Fam1 | PKP2 (GO: heart developm.) | 2 | TCF25 | ENSP00000263347.7:p.Ser390Phe | missense | neutral | rare | het in Fam1.III.2, Fam1.III.3, Fam1.II.1 | Negatively regulates SRF, whose increased expression causes cardiomyopathy in mice [43]. |
Fam1 | PKP2 (GO: neg. Reg. cell prolif.) | 3 | DAB2IP | ENSP00000259371.2:p.Asp10Gly | missense | neutral | rare | het in Fam1.III.2, Fam1.III.3, Fam1.II.1 | One variant in DAB2IP has been associated with coronary heart disease [44]. |
Fam1 | PKP2 (GO: neg. Reg. cell prolif.) | 4 | CTBP2 | ENSP00000357816.5:p.Gly70Arg | missense | neutral | common | het in Fam1.III.2, Fam1.III.3, Fam1.II.1 | Ctbp2-null mice have defective heart morphogenesis. CTBP2 may be a regulator of Wnt-mediated gene expression [45]. |
Fam2 | PKP2 (GO: neg. Reg. cell prolif.) | 1 | IRF1 | ENSP00000384406.1:p.Asn259Ser | missense | deleterious | rare | het in Fam2.II.1 and Fam2.I.1 | IRF1 is associated with cancer and a negative regulator of coronary artery smooth muscle cells [41] (OMIM *147575). |
Fam2 | PKP2 (GO: reg. of bicell. Tight. junction assembly) | 2 | MYO1C | ENSP00000412197.2:p.Gln766Lys | missense | neutral | rare | het in Fam2.II.1 and Fam2.I.1 | OMIM *606538 |
Fam2 | PKP2 (GO: cardiac muscle cell action pot.) | 3 | DMD | ENSP00000367948.2:p.Arg2151Trp | missense | neutral | common | hemi in Fam2.II.1, Fam2.I.1; het in Fam2.I.2 | Recessive mutations in DMD can cause muscle dystrophy (OMIM *300377). |
Fam2 | PKP2 (GO: heart development) | 4 | MKKS | ENSP00000382008.2:p.Ile339Val | missense | neutral | rare | het in Fam2.I.2 and Fam2.II.2 | Recessive mutations in MKKS can cause Bardet-Biedl syndrome (OMIM *604896). |
Fam2 | PKP2 (GO: neg. Reg. cell prolif.) | 5 | NOTCH2 | ENSP00000256646.2:p.Asp1327Gly | missense | neutral | common | het in Fam2.I.1 and Fam2.II.1 | This variant has been reported causal for Congenital heart disease as compound heterozygote with L2408H, which is absent in Fam2 [51]. |
Fam2 | PKP2 (GO: heart development) | 6 | PKD1 | ENSP00000456672.1:p.Arg198Trp | missense | neutral | rare | het in Fam2.II.1 and Fam2.I.1 | Dominant mutations have been associated with polycystic kidney disease (OMIM *601313). |
Fam2 | PKP2 (PPI / GO: pos. Reg. sodium ion) | 7 | SCN5A | ENSP00000398962.2:p.His558Arg | missense | neutral | common | het in Fam2.I.1, Fam2.I.2, Fam2.II.2, Fam1.II.3 | This variant has been reported causal for isolated conduction disease as compound heterozygote with T215I, which is absent in Fam2 [52]. |
Fam2 | PKP2 (GO: neg. Reg. cell prolif.) | 8 | MYOCD | ENSP00000341835.4:p.Gln304del | inframe deletion | neutral | common | het in Fam2.II.1 and Fam2.I.1 | Cardiac muscle-specific transcriptional coactivator of serum response factor. Mutations have been associated with hypertrophic cardiomypathy (OMIM *606127). |
Fam2 | PKP2 (PPI) | 9 | DSC1 | ENSP00000257198.5:p.Cys848Phe | missense | neutral | common | het in Fam2.II.1 and Fam2.I.1 | Desmosomal protein desmocolin 1 (*OMIM 125643). |
Fam2 | PKP2 (PPI) | 10 | DROSHA | ENSP00000339845.3:p.Ser321Leu | missense | neutral | common | hom in Fam2.I.2, Fam2.II.2; het in all others except Fam1.II.2 | Ribonuclease III. Mutations have been associated with cancer (OMIM *608828). |