Supplementary material J Med Genet

Supplementary tables

Supplementary Table 1. List of 522 genes in the heart gene panel

ABCC6 C5orf42 CUL3 FHL1 IGFBP7 MAT2A NR5A1 PTCH1 SKI TMEM43 ABCC9 CACNA1C CUL4B FIG4 IL10 MATR3 NRAS PTCH2 SLC19A2 TMEM67 ACE CACNA1D DAPK3 FKBP14 INVS MCTP2 NRXN1 PTEN SLC29A3 TNNC1 ACTA2 CACNA2D1 DCHS1 FKTN IRF6 MED12 NSD1 PTF1A SLC2A10 TNNI3 ACTB CACNB2 DDX11 FLNA IRX4 MED13L NSDHL PTH1R SLC35B2 TNNT2 ACTC1 CALM1 DDX3X FLNB JAG1 MEGF8 NUB1 PTPN11 SLCO2A1 TNS1 ACTG1 CALM2 DDX59 FOXC1 JPH2 MEOX1 OFD1 RAB10 SLMAP TP63 ACTN2 CALM3 DES FOXC2 JUP MESP1 ORC1 RAB23 SMAD2 TPM1 ACVR1 CALR3 DHCR24 FOXE3 KANSL1 MFAP5 ORC4 RAF1 SMAD3 TRDN ACVR2B CASQ2 DHCR7 FOXF1 KAT6B MGAT2 ORC6 RAI1 SMAD6 TRIM32 ADNP CAV3 DIS3L2 FOXH1 KCNA5 MGP PACS1 RANGRF SMARCA2 TRPM4 AGT CBL DLL3 FRAS1 KCND3 MIB1 PAFAH1B1 RARB SMARCA4 TRPV4 AKAP9 CCBE1 DLX5 FREM2 KCNE1 MID1 PAX1 RBM10 SMARCB1 TSR2 AKT3 CCDC103 DNAAF3 FTO KCNE1L MIR17HG PAX3 RBM20 SMARCE1 TTC37 ALDH18A1 CCDC114 DNAH11 G6PC3 KCNE2 MKKS PAX6 RBM8A SMC1A TTC8 ALDH1A2 CCDC151 DNAH5 GALNS KCNE3 MKS1 PCNT RECQL4 SNAI3 TTN ALG8 CCDC39 DNAI1 GATA3 KCNH2 MMP2 PDGFRB RELN SNRPB TTR ALPK3 CCDC40 DNMT3A GATA4 KCNJ2 MMP21 PDHA1 REN SNTA1 TUBA1A AMER1 CD96 DNMT3B GATA5 KCNJ5 MMP23A PDX1 RFX6 SOS1 TWIST1 ANK2 CDK13 DOCK6 GATA6 KCNJ8 MPDZ PEX1 RIT1 SOX10 TWIST2 ANKRD1 CDKN1C DSC2 GBA KCNQ1 MPLKIP PEX10 RMRP SOX2 UBE2B ANKRD11 CENPJ DSG1 GDF1 KDM5A MSX1 PEX2 RNF135 SOX9 UBR1 ARID1A CEP290 DSG2 GDF6 KDM5B MTCH1 PHF21A RNF20 SPRED1 USP34 ARID1B CEP57 DSP GEMIN2 KDM5C MYBPC3 PHGDH RNU4ATAC SRCAP USP44 ARL6 CFC1 DYNC2H1 GGCX KDM6A MYCN PIEZO2 ROR2 SRD5A3 VCL ASPH CHD4 DYRK1A GJA1 KIAA0196 MYH11 PIGF RPL35A STAMBP VEGFA ASXL1 CHD7 DYX1C1 GJA5 KIAA1279 MYH6 PIGL RPS11 STRA6 VEGFB ATIC CHRNA1 EBP GLA KIF11 MYH7 PIGN RPS17 SUPT5H VEGFC ATP7A CHRNB1 ECE1 GLB1 KIF7 MYH9 PIGT RPS19 SUV420H1 VIPAS39 ATR CHRNG EDN3 GLI3 KMT2A MYL2 PIGV RPS24 TAB2 VPS13B ATRX CHST3 EDNRB GLMN KMT2D MYL3 PIK3CA RPS5 TAF2 VPS33B AXIN1 CHUK EFEMP2 GPC3 KRAS MYLK PIK3R2 RPS7 TALDO1 WDR35 AXIN2 CITED2 EFTUD2 GPC6 KRT1 MYOZ2 PITX1 RRAS TAZ WDR5 B3GALT6 CNTNAP2 EHMT1 GPD1L LAMA4 MYPN PITX2 RUNX1 TBC1D24 WDR60 B3GALTL COG4 ELN GPX4 LAMP2 NAA15 PKD1 RYR2 TBC1D32 WNT4 B3GAT3 COG8 EMD GRHL3 LBR NEK1 PKD2 SALL1 TBX1 WNT5A BAG3 COL18A1 EMG1 HAND1 LDB3 NEXN PKP2 SALL4 TBX2 WNT7A BBS1 COL2A1 EOGT HAND2 LEFTY2 NFATC1 PLD1 SATB2 TBX20 WT1 BBS10 COL3A1 EP300 HCCS LIFR NFIX PLN SCLT1 TBX3 YAP1 BBS12 COLEC11 ESCO2 HCN4 LIG4 NIPBL PLXND1 SCN10A TBX5 ZBTB24 BBS2 COX7B EVC HES7 LMBR1 NKX2 PMM2 SCN1B TCAP ZEB2 BBS4 CREBBP EVC2 HEY2 LMCD1 NKX2-5 POLR1D SCN2B TCOF1 ZFPM2 BBS5 CRELD1 EZH2 HGD LMNA NKX2-6 PORCN SCN3B TCTN3 ZIC3 BBS9 CRELD2 FAM20C HGSNAT LMX1B NODAL PPA2 SCN4B TDGF1 ZMPSTE24 BCL9 CRKL FAM58A HOXA1 LRP2 NOS1 PPP3CA SCN5A TFAP2B ZNF236 BCOR CRYAA FBLN5 HPGD LRP5 NOTCH1 PQBP1 SDCCAG8 TGFB2 BHLHA9 CRYAB FBN1 HRAS LTBP4 NOTCH2 PRDM16 SETBP1 TGFB3 BMP4 CRYBB1 FBN2 HSPG2 LZTR1 NOTCH3 PRKAG2 SF3B4 TGFBR1 BMPR2 CRYGD FGD1 HUWE1 MAFB NPHP1 PRKD1 SH3PXD2B TGFBR2 BMS1 CSRP3 FGF16 IDH1 MAP2K1 NPHP3 PRKG1 SHANK3 TGIF1 BRAF CTCF FGF8 IDS MAP2K2 NPHP4 PRPS1 SHH TLL1 BUB1 CTNNA3 FGFR2 IFT122 MAP3K7 NPPA PSAT1 SHOC2 TMCO1 C12orf57 CTSA FGFR3 IFT80 MASP1 NR2F2 PSPH SHROOM3 TMEM216

van Wijngaarden AL, et al. J Med Genet 2020;0:1–8. doi: 10.1136/jmedgenet-2019-106715 Supplementary material J Med Genet

Supplementary Table 2. List of variants of uncertain significance found in 95 probands with

mitral valve prolapse based on the heart gene panel

ID Gene Exon Allele Nucleotide Amino acid change % HGMD ClinVar change GnomAD 49 ACTN2 10 Htz c.883G>T p.(Glu295*) - - - 56 COL18A1 39 Htz c.4931A>C p.(Asn1644Thr) - - - 93 DSP 2 Htz c.273+5G>A p.(?) 0.029 Class 5 Class 3 123 DSP 2 Htz c.273+5G>A p.(?) 0.029 Class 5 Class 3 32 FBN1 59 Htz c.7412C>G p.(Pro2471Arg) 0.003 Class 4? Class 3 63 FBN1 35 Htz c.4447G>A p.(Gly1483Arg) - - Class 4 75 FBN2 13 Htz c.1826C>G p.(Thr609Ser) - - - 86 FBN2 13 Htz c.1826C>G p.(Thr609Ser) - - - 87 FBN2 13 Htz c.1826C>G p.(Thr609Ser) - - - 99 FBN2 41 Htz c.5225G>A p.(Arg1742Gln) 0.002 - - 8 FLNA 25 Htz c.4288G>C p.(Gly1430Arg) 0.001 - - 69 FLNA 25 Htz c.4150G>A p.(Gly1384Ser) - - - 81 LZTR1 19 Htz c.2263C>T p.(Arg755Trp) 0.001 - - 13 MYH6 22 Htz c.2928+5G>A p.(?) 0.175 Class 5 Class 2 and class 3 29 MYH6 29 Htz c.4136C>T p.(Thr1379Met) 0.056 Class 5 Class 2 and class 3 44 MYH6 24 Htz c.3154C>T p.(Arg1052*) 0.001 - Class 3 114 MYH6 22 Htz c.2842G>A p.(Glu948Lys) 0.002 - - 28 NKX2-5 2c Htz c.545T>A p.(Val182Asp) - - - 92 NKX2-5 2c Htz c.413G>T p.(Arg138Leu) - - - 103 NOTCH1 24 Htz c.3905G>A p.(Arg1302His) 0.004 - - 3 NOTCH3 4 Htz c.625G>A p.(Gly209Arg) 0.002 - - 39 NOTCH3 33 Htz c.6097C>A p.(Pro2033Thr) 0.004 - - 63 NPM3 4 Htz c.343C>T p.(Gln115*) 0.000 - - 3 PRDM16 11 Htz c.2855C>A p.(Thr952Lys) 0.001 - Class 3 37 RYR2 103 Htz c.14757-7_14757- p.(?) - Class 5 - 6delTCinsAT 21 SMAD6 2 Htz c.841C>G p.(Arg281Gly) 0.014 - Class 2 21 SNAI3 3 Htz c.795C>A p.(Tyr265*) 0.003 - - 35 TCOF1 21 Htz c.3283C>T p.(Gln1095*) - - - 64 TNS1 24 Htz c.4223A>G p.(Asn1408Ser) 0.001 - - 69 TPM1 5 Htz c.549_563+10del p.(Glu184_Gly188del) - - - 4 TTN 327 Htz c.80414A>C p.(Glu26805Ala) 0.003 - Class 3 37 TTN 327 Htz c.80717G>A p.(Arg26906Gln) 0.003 - Class 3 77 TTN 327 Htz c.80717G>A p.(Arg26906Gln) 0.003 - Class 3 118 TTN 141 Htz c.33580G>A p.(Val1119Met) 0.001 - Class 3 46 VEGFA 1 Htz c.405_408del p.(Asp135Glufs*38) - - - * Class 2 = likely benign, Class 3 = variant of uncertain significance, Class 4 = likely pathogenic,

Class 5 = pathogenic, and Htz = heterozygous

2

van Wijngaarden AL, et al. J Med Genet 2020;0:1–8. doi: 10.1136/jmedgenet-2019-106715