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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).
  1. a ACM: known ACM genes; PKP2: PKP2 related genes
  2. b PKP2-related genes are listed according to their rank from top to bottom
  3. cdeleterious: PROVEAN score < −2.5; neutral: PROVEAN score > = 2.5
  4. dcommon: ExAC AF > = 0.01; rare: ExAC AF < 0.01 or NA; ExAC: Exome Aggregation Consortium
  5. ehet: heterozygous; hom: homozygous; hemi: hemizygous. If an individual is not listed, his/her genotype is homozygous reference