Itga4 Cldn16 Cldn9 Cldn15 Cldn22 Ocln Esam

Supplementary material J Med Genet

Table S1. List of 263 genes included in the AGS-LEUK panel. Axonal Guidance Signaling genes as AGS and Leukocyte transvasation genes as LEUK. List of genes (AGS) List of genes (LEUK) ABLIM1 CLDN11 ACTR3 MMP14 ADAM11 MMP15 ADAM23 CTNNA1 ADAMTS1 ENSG00000130396 ADAMTS4 CLDN6 ADAMTS9 MMP24 ARHGEF15 ARHGAP12 ARHGEF6 DLC1 ARPC1B TIMP2 BDNF RAPGEF3 BMP1 F11R BMP4 CLDN23 BMP6 CLDN8 BMP7 JAM3 CXCL12 CLDN3 CXCR4 ARHGAP8 DPYSL5 ICAM1 EFNA1 MMP16 EFNA5 JAM2 ENPEP CLDN7 EPHA1 TIMP3 EPHA3 VCAM1 EPHA5 CLDN5 EPHA7 MSN EPHB1 NOX3 EPHB2 ACTC1 EPHB4 VAV2 FGFR2 CLDN10 FZD1 RAP1GAP FZD10 VAV3 FZD5 MAPK10 FZD6 CTNNA2 GAB1 CDH5 GLI1 PECAM1 GLI3 CTNND1 GNA14 ITGA4 GNAI1 CLDN16 GNAO1 CLDN9 GNAS CLDN15 GNB4 CLDN22 GNG11 OCLN GNG2 ESAM

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

GNG7 ACTB IGF1 CYBA IRS1 CTNNB1 IRS2 MMP9 ITGA3 MAPK14 ITGB1 MAPK11 LIMK1 MAPK12 LIMK2 MAPK13 LINGO1 PRKCB LRRC4C PXN MME BCAR1 MMP11 THY1 MMP2 ARHGAP5 MRAS MYL2 MYL9 MYLPF NFATC4 RAP1A NGFR RAP1B NOTUM VASP NRP1 ACTN4 NTN3 ACTN1 NTRK2 VCL NTRK3 RAPGEF4 PAK3 ITK PAK4 VAV1 PAPPA2 PDGFA PDGFC PIK3CB PIK3R1 PLCE1 PLCH1 PLCH2 PLXNA2 PLXNB1 PLXND1 PPP3CA PRKACB PRKAR2A PRKAR2B PRKCA PRKCZ PRKD3 ROBO2 SDC2 SDCBP

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SEMA3B SEMA3C SEMA3E SEMA3F SEMA4F SEMA4G SEMA5A SEMA6B SEMA6D SEMA7A SHC1 SLIT2 SLIT3 STK36 TUBA4A TUBB2B TUBB4A TUBB4B TUBB6 UNC5C UNC5D ENSG00000165197 WIPF1 WNT3 WNT5A WNT7A WNT7B NTNG1 NTNG2 LRRC4 NTN4 TRPC1 TRPC3 TRPC6 PPP3CB PPP3CC PPP3R1 NFATC2 NFATC3 PTK2 FYN RAC1 CDC42 ABLIM2 NCK1 PAK1 PAK2

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PAK6 RHOA ROCK1 ROCK2 PTPN11 EFNB1 EFNB2 EFNB3 EPHA4 ABL1 ENAH RASA1 KRAS NRAS MAPK1 RGS3 GNAI3 GNAI2 ROBO1 SRGAP2 SRGAP1 SRGAP3 SEMA3A PLXNA3 PLXNA4 CFL1 CFL2 RHOD DPYSL2 CDK5 GSK3B SEMA4D SEMA4B SEMA4C SEMA5B SEMA6A PLXNB2 RAF1 RRAS PLXNC1 PTCH1 SMO ILK BOC WNT5B FZD3 RYK

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

CAMK2D CAMK2B CAMK2G WNT4 PIK3CA PIK3R3 PDK1 PARD3 PARD6A PARD6G SSH1 SSH3 BMPR2 BMPR1B

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Table S2. Number of exonic variants found after variant calling and frequency filtering.

Exonic total 2194 Missense 1189 Synonymous 966 Stopgain 32 Stoploss 5 Startloss 2

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Table S3. List of all the genes considered from the missense analysis with OR > 1.

Missense CSVS Gene OR(CI) Pvalue PvalueIF SHC1 18.94 (7.75-55.68) 1.54398E-15 0.000334 NOX3 6.96 (3.87-12.91) 4.03682E-12 0.002338 PRKD3 2.03 (1.56-2.63) 8.35583E-08 0.026857 NTN4 7.22 (3.07-18.3) 7.52201E-07 0.04584 DLC1 2.15 (1.55-2.95) 2.76422E-06 0.062827 PTK2 4.74 (2.35-9.77) 4.13399E-06 0.069242 SEMA4F 1.84 (1.41-2.39) 5.53808E-06 0.074303 STK36 1.6 (1.28-1.98) 2.28373E-05 0.104459 BMP1 1.73 (1.34-2.24) 2.70986E-05 0.10883 EPHA5 1.91 (1.37-2.65) 0.00012908 0.157918 AP000349.1 1.98 (1.38-2.82) 0.000182601 0.171454 EPHA7 1.68 (1.28-2.2) 0.000192955 0.173708 NCK1 1.86 (1.33-2.58) 0.000215017 0.178215 ARPC1B 1.96 (1.35-2.81) 0.000320759 0.195868 IRS1 1.55 (1.2-1.98) 0.0005828 0.225397 PIK3CA 1.48 (1.16-1.87) 0.001560294 0.283608 PLXNA4 1.94 (1.27-2.92) 0.00162882 0.286448 RGS3 1.44 (1.14-1.81) 0.001948863 0.298597 PLCE1 1.55 (1.17-2.05) 0.00222802 0.307976 VCL 3.14 (1.41-6.89) 0.002846545 0.32586 SSH3 2 (1.23-3.21) 0.003293191 0.336955 ESAM 7.13 (1.52-44.19) 0.005039489 0.371373 ADAMTS4 1.47 (1.11-1.92) 0.005565848 0.379862 KCNQ3 1.99 (1.18-3.3) 0.00655371 0.394209 MLLT4 1.51 (1.11-2.04) 0.006963292 0.399656 PLXND1 1.76 (1.15-2.66) 0.007679725 0.4086 RHOD 1.8 (1.14-2.8) 0.009323239 0.426844 FZD6 5.94 (1.15-38.28) 0.015650912 0.479168 ROCK1 1.98 (1.1-3.49) 0.016506139 0.484846 DPYSL5 1.43 (1.05-1.94) 0.018133847 0.495025 ARHGAP5 1.83 (1.07-3.08) 0.020144781 0.506622 ARHGAP8 1.89 (1.03-3.35) 0.025288899 0.532482 SUCLG2 1.26 (1.02-1.55) 0.02973562 0.551559 GNA14 2.46 (1.03-5.66) 0.03197755 0.560297 ABL1 1.43 (1-2.02) 0.040398752 0.589145 RAF1 4.75 (0.8-32.46) 0.045892271 0.605354 SLIT2 4.75 (0.8-32.46) 0.045892271 0.605354 PARD6A 1.35 (0.99-1.81) 0.047497626 0.609782 EPHA3 1.27 (1-1.6) 0.04947228 0.615059 BMPR2 1.45 (0.98-2.1) 0.055591766 0.630352 MMP15 1.69 (0.91-3.06) 0.073463879 0.667979 FZD10 1.44 (0.93-2.18) 0.091178171 0.69812 BOC 1.95 (0.87-4.13) 0.09257319 0.700268 PLXNC1 1.36 (0.92-1.96) 0.095647475 0.704904 ACTN1 1.43 (0.93-2.15) 0.096315071 0.705893 FGFR2 2.19 (0.79-5.73) 0.107026958 0.720982

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SEMA3C 2.37 (0.69-7.49) 0.113796227 0.729834 SEMA5B 1.39 (0.9-2.1) 0.119942558 0.737468 RAPGEF4 3.56 (0.48-26.58) 0.124620138 0.743043 WNT7A 3.56 (0.48-26.58) 0.124620138 0.743043 SEMA3F 3.56 (0.48-26.58) 0.124620138 0.743043 PLCH1 3.56 (0.48-26.58) 0.124620138 0.743043 CLDN11 3.56 (0.48-26.58) 0.124620138 0.743043 LRRC4 3.56 (0.48-26.58) 0.124620138 0.743043 NTRK2 3.56 (0.48-26.58) 0.124620138 0.743043 WNT5B 3.56 (0.48-26.58) 0.124620138 0.743043 TRPC6 1.17 (0.94-1.45) 0.162248864 0.781938 ITGA4 1.98 (0.52-6.59) 0.206503116 0.817935 GLI1 1.98 (0.52-6.59) 0.206503116 0.817935 PIK3R3 2.37 (0.49-10.02) 0.241385079 0.841262 PAPPA2 2.37 (0.49-10.02) 0.241385079 0.841262 LIMK2 2.37 (0.49-10.02) 0.241385079 0.841262 SEMA4G 1.24 (0.81-1.86) 0.286124599 0.866502 ROBO2 2.37 (0.2-20.7) 0.303796962 0.875311 BMPR1B 2.37 (0.2-20.7) 0.303796962 0.875311 UNC5C 2.37 (0.2-20.7) 0.303796962 0.875311 ITK 2.37 (0.2-20.7) 0.303796962 0.875311 MAPK14 2.37 (0.2-20.7) 0.303796962 0.875311 GLI3 2.37 (0.2-20.7) 0.303796962 0.875311 LIMK1 2.37 (0.2-20.7) 0.303796962 0.875311 PTCH1 2.37 (0.2-20.7) 0.303796962 0.875311 LINGO1 2.37 (0.2-20.7) 0.303796962 0.875311 PRKCB 2.37 (0.2-20.7) 0.303796962 0.875311 ARHGEF15 2.37 (0.2-20.7) 0.303796962 0.875311 MMP24 2.37 (0.2-20.7) 0.303796962 0.875311 CTNND1 1.56 (0.54-4.01) 0.3171239 0.881582 SRGAP1 1.4 (0.63-2.91) 0.334653758 0.889384 PARD3 1.32 (0.64-2.58) 0.382814 0.908535 ALDH5A1 1.15 (0.79-1.66) 0.404046407 0.916048 NRP1 1.78 (0.29-8.34) 0.422095294 0.922041 SEMA6B 1.78 (0.29-8.34) 0.422095294 0.922041 PLXNA2 1.16 (0.74-1.78) 0.44653005 0.929624 EPHA1 1.58 (0.35-5.67) 0.499948603 0.944303 PAK4 1.58 (0.35-5.67) 0.499948603 0.944303 VAV3 1.27 (0.55-2.71) 0.554291737 0.956916 ADAM23 1.18 (0.12-6.63) 0.690574025 0.980241 SEMA3E 1.18 (0.12-6.63) 0.690574025 0.980241 FZD3 1.18 (0.12-6.63) 0.690574025 0.980241 MAPK13 1.18 (0.21-4.75) 0.733336354 0.985488 FZD5 1.05 (0.76-1.43) 0.752627915 0.987568 SEMA6D 1.11 (0.32-3.18) 0.794183285 0.991465 EPHB2 1.18 (0.02-14.75) 1 1 F11R 1.18 (0.02-14.75) 1 1 ENAH 1.18 (0.02-14.75) 1 1 PDK1 1.18 (0.02-14.75) 1 1 WIPF1 1.18 (0.02-14.75) 1 1

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ROBO1 1.18 (0.02-14.75) 1 1 RASA1 1.18 (0.02-14.75) 1 1 UNC5D 1.18 (0.02-14.75) 1 1 SEMA4D 1.18 (0.02-14.75) 1 1 ARHGAP12 1.18 (0.02-14.75) 1 1 MYL2 1.18 (0.02-14.75) 1 1 MMP14 1.18 (0.02-14.75) 1 1 SEMA4B 1.18 (0.02-14.75) 1 1 CLDN6 1.18 (0.02-14.75) 1 1 AFG3L2 1.18 (0.02-14.75) 1 1 ADAMTS1 1.18 (0.02-14.75) 1 1

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Missense EXAC GLOBAL Gene OR(CI) Pvalue PvalueIF ARHGAP8 2.19 (1.91-2.51) 7.00E-29 0 NFATC3 2.12 (1.81-2.48) 2.39142E-19 0.05893 PLCE1 2.92 (2.32-3.64) 3.62149E-17 0.11878 DPYSL5 2.96 (2.34-3.71) 6.61828E-17 0.217071 GAB1 3.8 (2.86-4.97) 7.71941E-17 0.217071 ARHGAP5 4.16 (3.06-5.54) 2.21559E-16 0.223762 CYBA 4.13 (3.02-5.55) 1.77572E-15 0.245088 GLI3 1.87 (1.6-2.17) 3.16683E-15 0.251549 PLXNB1 2.86 (2.24-3.62) 5.46446E-15 0.257387 IRS1 2.19 (1.81-2.63) 1.45617E-14 0.268695 EPHA5 2.21 (1.82-2.67) 2.17548E-14 0.273469 UNC5C 3.06 (2.29-4.01) 2.15685E-12 0.334217 PLXNA4 2.19 (1.77-2.69) 4.93217E-12 0.346479 BMP1 2.09 (1.7-2.54) 1.11483E-11 0.359002 ACTN1 2.01 (1.65-2.44) 3.57942E-11 0.377689 LRRC4 2.8 (2.08-3.7) 1.60896E-10 0.403175 VAV3 3.41 (2.38-4.77) 5.6734E-10 0.425831 ABL1 2.47 (1.88-3.2) 7.1472E-10 0.430115 PLCH1 2.35 (1.81-3.02) 1.35133E-09 0.442149 RGS3 1.61 (1.38-1.87) 3.09394E-09 0.45829 PRKD3 1.93 (1.55-2.38) 8.91783E-09 0.479748 MLLT4 1.94 (1.55-2.39) 1.16957E-08 0.485399 GNAS 1.87 (1.51-2.29) 2.14462E-08 0.498266 NTN4 3.47 (2.29-5.08) 3.72412E-08 0.510262 ADAMTS1 1.88 (1.51-2.31) 3.82747E-08 0.510864 SUCLG2 1.69 (1.4-2.03) 6.3078E-08 0.521975 SEMA3A 2.73 (1.9-3.8) 1.51589E-07 0.542033 PLXNC1 1.68 (1.39-2.03) 1.74139E-07 0.545272 SRGAP2 2.63 (1.87-3.63) 1.82617E-07 0.546387 PLXNA3 1.95 (1.52-2.48) 4.4108E-07 0.567455 CLDN8 1.83 (1.45-2.3) 7.58833E-07 0.580796 EPHA3 1.7 (1.38-2.07) 8.20948E-07 0.582755 ESAM 1.71 (1.38-2.1) 1.50277E-06 0.598015 STK36 1.49 (1.27-1.75) 2.02374E-06 0.605663 BMP7 1.81 (1.41-2.31) 5.91108E-06 0.633961 SEMA6A 1.8 (1.39-2.29) 1.13873E-05 0.651862 PARD3 2.92 (1.83-4.46) 1.26968E-05 0.654877 BMPR2 1.96 (1.4-2.68) 9.32906E-05 0.712364 RHOD 2.16 (1.47-3.08) 9.44276E-05 0.712726 DLC1 1.35 (1.15-1.57) 0.000167982 0.730128 SEMA4F 1.45 (1.18-1.77) 0.000452463 0.760878 PLXNB2 1.6 (1.23-2.07) 0.00051694 0.76509 ADAM23 2.3 (1.42-3.53) 0.000543668 0.766688 EPHA1 1.52 (1.19-1.91) 0.000576999 0.768578 SLIT2 2.1 (1.37-3.09) 0.000651504 0.772447 ARHGEF15 1.74 (1.24-2.39) 0.00122995 0.792926

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PTK2 2.1 (1.31-3.19) 0.001374512 0.796548 MMP15 1.82 (1.24-2.57) 0.001578641 0.800424 SEMA4D 1.3 (1.1-1.53) 0.001795958 0.80531 MME 1.85 (1.24-2.68) 0.002454424 0.815625 ICAM1 1.45 (1.12-1.84) 0.004090055 0.832667 ROCK1 1.97 (1.21-3.06) 0.004989074 0.839352 CDH5 1.36 (1.09-1.67) 0.005264072 0.841163 PAK1 1.81 (1.18-2.67) 0.005718253 0.843959 SEMA5A 1.35 (1.09-1.67) 0.005784083 0.844346 ITGA3 1.33 (1.08-1.62) 0.006172979 0.846548 MAPK13 1.85 (1.13-2.87) 0.010309764 0.863999 SEMA4G 1.28 (1.06-1.54) 0.011365523 0.867332 BCAR1 1.43 (1.07-1.87) 0.012430037 0.870397 SHC1 1.27 (1.04-1.54) 0.016446763 0.880001 NRP1 1.65 (1.03-2.53) 0.026582399 0.896511 AP SEMA4B 1.43 (1.01-1.96) 0.036400212 0.90732 FZD6 1.43 (1-1.98) 0.038535113 0.909277 ITGA4 1.95 (0.92-3.64) 0.044397366 0.914135 PAK6 1.6 (0.98-2.47) 0.049720022 0.918012 ACTN4 1.29 (0.98-1.67) 0.055802614 0.921955 PLXNA2 1.15 (0.97-1.35) 0.098934193 0.941311 PLCH2 1.21 (0.91-1.57) 0.167732079 0.958605 EPHB2 1.36 (0.8-2.18) 0.207880506 0.965379 ADAMTS4 1.14 (0.92-1.41) 0.217398172 0.966766 MMP9 1.19 (0.86-1.59) 0.258496732 0.972035 SRGAP1 1.19 (0.82-1.69) 0.293818228 0.975816 PDGFC 1.39 (0.63-2.67) 0.317308426 0.97803 NFATC4 1.25 (0.73-1.99) 0.349616701 0.980753 SSH1 1.18 (0.73-1.81) 0.41023496 0.985049 GNA14 1.25 (0.57-2.4) 0.450648701 0.987439 MMP14 1.13 (0.69-1.77) 0.545438894 0.991912 PAK4 1.07 (0.82-1.37) 0.598408368 0.993857 CTNNA1 1.18 (0.43-2.61) 0.649567009 0.995424 ARPC1B 1 (0.74-1.33) 0.943110469 0.999887

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Missense EXAC NFE Gene OR(CI) Pvalue PvalueIF ARHGAP5 2.78 (2.04-3.71) 5.98107E-10 0.246425 UNC5C 2.61 (1.95-3.44) 1.36239E-09 0.261318 CLDN8 2.09 (1.65-2.63) 5.6093E-09 0.289012 DLC1 1.58 (1.35-1.85) 1.22735E-08 0.305549 PLCE1 2 (1.58-2.49) 1.33495E-08 0.307378 GAB1 2.36 (1.77-3.08) 1.35006E-08 0.307624 BMP1 1.84 (1.5-2.25) 1.49133E-08 0.309805 PLXNC1 1.75 (1.44-2.12) 2.69087E-08 0.323056 DPYSL5 1.99 (1.57-2.49) 3.72671E-08 0.330602 PLXNB1 2.05 (1.6-2.59) 3.94324E-08 0.331928 IRS1 1.72 (1.42-2.07) 5.2504E-08 0.338731 PARD3 4.19 (2.58-6.5) 5.34966E-08 0.33918 PRKD3 1.85 (1.49-2.28) 7.45676E-08 0.347251 ADAMTS9 1.59 (1.34-1.88) 1.54726E-07 0.365652 EPHA5 1.69 (1.39-2.04) 2.27819E-07 0.375786 STK36 1.54 (1.31-1.81) 2.6118E-07 0.379429 ARHGAP8 1.43 (1.24-1.63) 3.21254E-07 0.385014 PLXNA4 1.76 (1.42-2.17) 3.72757E-07 0.389074 SEMA4B 2.55 (1.8-3.52) 3.7874E-07 0.389512 ICAM1 1.97 (1.52-2.51) 4.65268E-07 0.395205 NTN4 3.05 (2-4.49) 5.92347E-07 0.401988 PLCH1 1.99 (1.52-2.55) 6.96317E-07 0.406594 GLI3 1.47 (1.26-1.71) 8.04638E-07 0.410754 ACTN1 1.66 (1.36-2.02) 8.81687E-07 0.413407 ABL1 2.01 (1.52-2.6) 1.43221E-06 0.427756 VAV3 2.42 (1.68-3.39) 3.50115E-06 0.455452 CYBA 2.1 (1.54-2.82) 4.81632E-06 0.46574 ADAMTS1 1.63 (1.31-2.02) 1.4423E-05 0.502829 NFATC3 1.42 (1.21-1.66) 1.57881E-05 0.506008 LRRC4 1.94 (1.44-2.56) 1.81039E-05 0.510855 EPHA7 1.65 (1.3-2.06) 3.87598E-05 0.538614 SEMA3C 2.44 (1.54-3.72) 0.000164715 0.595234 PLXNA2 1.37 (1.16-1.62) 0.000253449 0.613109 LIMK2 1.92 (1.34-2.67) 0.00031216 0.62192 SSH3 1.81 (1.29-2.47) 0.000468719 0.639432 GNAS 1.46 (1.18-1.79) 0.000489582 0.641333 SEMA3A 1.84 (1.28-2.56) 0.000812817 0.663825 EPHA3 1.4 (1.14-1.72) 0.001443426 0.690102 SRGAP2 1.72 (1.22-2.37) 0.001781449 0.69994 MMP11 2.16 (1.28-3.44) 0.003369657 0.730423 RHOD 1.74 (1.18-2.49) 0.00361225 0.733808 BMP7 1.46 (1.13-1.86) 0.003866507 0.737132 ITGA3 1.35 (1.09-1.64) 0.004741627 0.747168 ESAM 1.35 (1.09-1.66) 0.005560137 0.755069 ACTN4 1.47 (1.11-1.91) 0.006143372 0.760048 MLLT4 1.36 (1.09-1.68) 0.006571805 0.763426

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

SEMA4F 1.32 (1.07-1.61) 0.007982554 0.773226 BCAR1 1.45 (1.08-1.91) 0.011271005 0.79081 ADAM23 1.77 (1.09-2.73) 0.014315221 0.803137 MMP9 1.46 (1.06-1.97) 0.015897906 0.808577 ARHGEF15 1.5 (1.06-2.06) 0.019269397 0.818603 ADAMTS4 1.28 (1.03-1.58) 0.025102977 0.832485 SLIT2 1.6 (1.04-2.36) 0.025837761 0.834006 PTK2 1.59 (1-2.43) 0.044429286 0.862733 SUCLG2 1.2 (1-1.45) 0.049174721 0.868135 ARPC1B 1.34 (0.99-1.78) 0.049749931 0.868754 EPHA1 1.26 (0.99-1.59) 0.055367288 0.874452 PLXNA3 1.24 (0.96-1.57) 0.084562821 0.896981 NRP1 1.41 (0.87-2.16) 0.123012377 0.916746 KCNQ3 1.34 (0.9-1.92) 0.137325497 0.922489 AP000349.1 1.2 (0.93-1.54) 0.143441588 0.924751 ROCK1 1.41 (0.86-2.18) 0.146584715 0.925874 MME 1.3 (0.87-1.89) 0.1664898 0.932433 SEMA6A 1.18 (0.91-1.51) 0.184075778 0.937554 BMPR2 1.24 (0.89-1.7) 0.189909434 0.939134 GNA14 1.58 (0.71-3.08) 0.197371627 0.941079 SRGAP1 1.26 (0.86-1.79) 0.199279861 0.941563 ABLIM1 1.34 (0.76-2.21) 0.2397765 0.950752 PLXNB2 1.17 (0.89-1.5) 0.2425237 0.951309 MAPK13 1.3 (0.8-2.02) 0.251950666 0.953168 RGS3 1.09 (0.93-1.27) 0.270332745 0.956567 HDAC10 1.1 (0.89-1.36) 0.35276482 0.968936 MMP15 1.17 (0.8-1.66) 0.390665307 0.97343 VAV1 1.09 (0.87-1.36) 0.397802551 0.97421 ITGA4 1.25 (0.59-2.35) 0.469437952 0.981058 SHC1 1.07 (0.87-1.3) 0.482517298 0.982138 PAPPA2 1.14 (0.71-1.76) 0.486312754 0.982443 SEMA5A 1.06 (0.85-1.31) 0.547040472 0.986834 ALDH5A1 1.09 (0.79-1.46) 0.584602122 0.989138 PAK1 1.11 (0.72-1.63) 0.603245453 0.990177 EPHB2 1.12 (0.66-1.8) 0.609935429 0.990533 CDH5 1.05 (0.84-1.29) 0.667042787 0.993259 SEMA4D 1.03 (0.87-1.21) 0.738720986 0.995942 FZD6 1.02 (0.72-1.43) 0.865011677 0.998944 PAK6 1.01 (0.62-1.57) 0.910326362 0.999537

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Table S4. List of all the genes considered from the CADD>20 analysis with OR > 1.

CADD20 CSVS Gene OR(CI) Pvalue PvalueIF NOX3 7.56 (4.02-14.77) 9.96782E-12 0.000462 NTN4 9.61 (3.56-30.08) 5.10248E-07 0.015289 PTK2 6.57 (2.22-21.7) 0.000180989 0.09794 PLXND1 1.76 (1.15-2.66) 0.007679725 0.307949 EPHA7 1.62 (1.1-2.36) 0.01284883 0.358487 ARHGAP8 1.89 (1.03-3.35) 0.025288899 0.43634 ARHGAP5 1.76 (1.01-2.97) 0.040043138 0.497209 SLIT2 4.75 (0.8-32.46) 0.045892271 0.516571 STK36 1.38 (0.99-1.9) 0.048792723 0.525472 FZD10 1.44 (0.93-2.18) 0.091178171 0.623183 RGS3 3.56 (0.48-26.58) 0.124620138 0.676484 VCL 3.56 (0.48-26.58) 0.124620138 0.676484 WNT5B 3.56 (0.48-26.58) 0.124620138 0.676484 SUCLG2 2.37 (0.49-10.02) 0.241385079 0.796548 SEMA6D 2.37 (0.49-10.02) 0.241385079 0.796548 PRKD3 2.37 (0.2-20.7) 0.303796962 0.839242 UNC5C 2.37 (0.2-20.7) 0.303796962 0.839242 EPHA1 2.37 (0.2-20.7) 0.303796962 0.839242 GLI1 1.78 (0.29-8.34) 0.422095294 0.898695 SEMA6B 1.78 (0.29-8.34) 0.422095294 0.898695 PLXNA2 1.16 (0.74-1.78) 0.44653005 0.908433 ROCK1 1.18 (0.12-6.63) 0.690574025 0.974079 RHOD 1.18 (0.21-4.75) 0.733336354 0.980947 PLXNA4 1.09 (0.26-3.55) 0.776141673 0.986689 ENAH 1.18 (0.02-14.75) 1 1 PDK1 1.18 (0.02-14.75) 1 1 UNC5D 1.18 (0.02-14.75) 1 1 SEMA4D 1.18 (0.02-14.75) 1 1 MMP14 1.18 (0.02-14.75) 1 1

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

CADD20 EXAC GLOBAL Gene OR(CI) Pvalue PvalueIF PLXND1 2.02 (1.75-2.32) 2.86678E-22 3.3611E-11 UNC5C 2.16 (1.82-2.56) 6.44629E-22 1.04001E-11 DLC1 8.55 (5.66-12.54) 5.26029E-18 7.2401E-08 PLXNB1 4.06 (3.04-5.33) 1.49508E-17 1.15386E-07 DPYSL5 2.96 (2.34-3.71) 6.61828E-17 0.117446545 EPHA5 2.21 (1.82-2.67) 2.17548E-14 0.16236107 IRS1 2.18 (1.77-2.66) 1.81541E-12 0.212844045 ROBO2 7.31 (4.4-11.55) 1.50088E-11 0.242144962 BMP1 6.81 (4.16-10.64) 1.77755E-11 0.244657102 PLCE1 1.65 (1.42-1.9) 3.29144E-11 0.254023787 GAB1 3.75 (2.59-5.29) 1.4021E-10 0.277471856 LRRC4 2.88 (2.12-3.83) 1.89833E-10 0.282637013 PLXNB2 1.51 (1.3-1.76) 3.26154E-08 0.386201074 NTN4 3.47 (2.29-5.08) 3.72412E-08 0.389308416 ADAMTS1 1.88 (1.51-2.31) 3.82747E-08 0.389952732 ARHGAP8 2.95 (2.04-4.15) 5.24657E-08 0.397451006 ARHGAP5 4.27 (2.63-6.61) 5.42574E-08 0.398257592 SEMA3A 2.92 (2.01-4.13) 9.39638E-08 0.411675356 PLXNA3 1.95 (1.52-2.48) 4.4108E-07 0.45184012 ROBO1 2.03 (1.56-2.62) 4.62951E-07 0.453156037 EPHA3 1.7 (1.38-2.07) 8.20948E-07 0.469013279 SEMA4F 3.88 (2.33-6.11) 8.86637E-07 0.471184074 LIMK2 2.47 (1.7-3.48) 3.927E-06 0.515078102 ESAM 1.67 (1.34-2.05) 6.34391E-06 0.530028513 PLCH1 4.16 (2.28-7.04) 8.6359E-06 0.539856735 EPHB1 6.32 (2.94-12.12) 9.72939E-06 0.543701198 WDR92 2.63 (1.72-3.86) 1.06258E-05 0.54655942 GNAS 1.97 (1.45-2.61) 2.18106E-05 0.570408257 PLXNA2 1.38 (1.19-1.61) 3.55208E-05 0.587125337 VAV2 2.44 (1.57-3.62) 8.36052E-05 0.617547391 RAPGEF4 7.17 (2.77-15.67) 9.97659E-05 0.624002151 NTNG2 3.02 (1.73-4.93) 0.000108715 0.627161631 GLI3 1.65 (1.28-2.12) 0.000140994 0.636810041 CLDN7 6.08 (2.36-13.18) 0.000256586 0.659528867 ACTN1 2 (1.37-2.81) 0.000275698 0.662301627 ARHGEF15 1.84 (1.3-2.54) 0.000503303 0.685926556 SEMA4D 1.28 (1.11-1.47) 0.000581934 0.691729869 PXN 2.74 (1.48-4.68) 0.001024246 0.714719379 MME 1.95 (1.28-2.85) 0.001389385 0.727371773 OCLN 2.27 (1.31-3.69) 0.002665516 0.754989938 LRRC4C 3.48 (1.47-7.05) 0.003010148 0.760229672 SEMA6B 6.52 (1.69-18.02) 0.00436656 0.776420392 SLIT2 2.19 (1.23-3.61) 0.0047096 0.779740983

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

MMP9 3.99 (1.43-9.03) 0.005153295 0.783706495 ADAM23 2.49 (1.22-4.53) 0.006642926 0.79496094 BDNF 1.25 (1.06-1.46) 0.007133583 0.798137712 ENAH 3.76 (1.19-9.14) 0.012949018 0.82500481 VCL 3.76 (1.19-9.14) 0.012949018 0.82500481 MAPK13 1.87 (1.1-3) 0.014113474 0.828924267 STK36 1.34 (1.05-1.7) 0.015541449 0.833321608 PLXNA4 1.42 (1.05-1.88) 0.018655793 0.841682814 PIK3R3 4.09 (1.08-11) 0.019622029 0.844000437 BMP6 3.75 (0.99-10.05) 0.025559492 0.85617035 SHC1 3.46 (0.92-9.26) 0.03246759 0.867226381 EPHA1 1.34 (1.01-1.76) 0.035278716 0.871070556 ACTN4 1.55 (1-2.29) 0.03578722 0.871733329 MUS81 2.83 (0.9-6.81) 0.036576602 0.872743881 SRGAP3 2.51 (0.9-5.59) 0.037766465 0.874226876 NTRK2 3.22 (0.86-8.58) 0.040365092 0.877310252 SEMA6D 3.22 (0.86-8.58) 0.040365092 0.877310252 CLDN3 2.42 (0.87-5.39) 0.043471336 0.880746164 NRP1 1.61 (0.96-2.54) 0.05467731 0.891373491 MMP15 1.63 (0.94-2.65) 0.058879563 0.894801457 PARD3 1.88 (0.8-3.78) 0.08334459 0.910835812 CLDN11 2.81 (0.57-8.57) 0.097764016 0.918150308 SEMA3E 1.17 (0.96-1.42) 0.119924795 0.927443889 PRKAR2A 2.41 (0.49-7.31) 0.13504611 0.932797204 ABL1 1.48 (0.73-2.68) 0.19378636 0.948764447 PAK6 1.33 (0.81-2.05) 0.202468099 0.950660967 RRAS 1.58 (0.63-3.3) 0.225946302 0.955359303 GNAI3 3.79 (0.09-24.07) 0.241622642 0.958193276 SEMA6A 1.14 (0.89-1.46) 0.265554924 0.962127037 MLLT4 1.25 (0.81-1.83) 0.273702163 0.963370497 GNAI1 1.8 (0.48-4.72) 0.293051331 0.966151511 HDAC10 1.31 (0.74-2.15) 0.308616759 0.968229052 NFATC4 1.25 (0.73-1.99) 0.349616701 0.973118978 PAPPA2 1.22 (0.68-2.04) 0.387118906 0.976972151 KCNQ3 1.14 (0.8-1.57) 0.431152142 0.980882718 GNA14 1.25 (0.57-2.4) 0.450648701 0.982432851 FGFR2 1.38 (0.5-3.05) 0.460344808 0.983166407 SEMA5A 1.2 (0.68-1.97) 0.485453782 0.984958528 EPHA7 1.08 (0.79-1.44) 0.591679954 0.991078151 BMPR1B 1.02 (0.03-5.88) 0.628512978 0.992735532 CTNNA1 1.18 (0.43-2.61) 0.649567009 0.993590433 JAM2 1.14 (0.42-2.53) 0.657483608 0.993895364 MMP14 1.03 (0.87-1.22) 0.728088403 0.996242208 GNB4 1.02 (0.28-2.66) 0.799564222 0.997993938 RAPGEF3 1.02 (0.89-1.17) 0.810579949 0.998212342 ITGA3 1.01 (0.84-1.21) 0.855103415 0.998961888 ARPC1B 1 (0.74-1.33) 0.943110469 0.9998414

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

CADD20 EXAC NFE Gene OR(CI) Pvalue PvalueIF DLC1 5.87 (3.86-8.65) 1.37152E-13 0.094963 PLXNB1 2.8 (2.1-3.69) 5.15352E-11 0.156578 PLCE1 1.62 (1.4-1.87) 1.71733E-10 0.173256 UNC5C 1.67 (1.41-1.99) 5.13538E-10 0.189951 PLXND1 1.52 (1.32-1.75) 4.64274E-09 0.228448 ROBO2 5.21 (3.12-8.3) 6.64066E-09 0.235393 BMP1 4.57 (2.78-7.17) 2.52909E-08 0.263221 DPYSL5 1.99 (1.57-2.49) 3.72671E-08 0.271874 IRS1 1.79 (1.45-2.19) 8.34361E-08 0.290765 EPHA5 1.69 (1.39-2.04) 2.27819E-07 0.316106 EPHB1 10.24 (4.52-21.08) 2.88532E-07 0.322372 NTN4 3.05 (2-4.49) 5.92347E-07 0.342199 ENAH 47.16 (10.12-236.35) 1.3516E-06 0.366394 PLXNB2 1.44 (1.23-1.68) 1.50071E-06 0.369579 JAM2 22.63 (6.74-68.8) 1.93664E-06 0.377452 SEMA3C 2.86 (1.86-4.23) 2.97323E-06 0.391052 GAB1 2.4 (1.65-3.38) 7.50809E-06 0.422062 ADAMTS1 1.63 (1.31-2.02) 1.4423E-05 0.44531 LRRC4 1.96 (1.44-2.62) 2.23231E-05 0.461536 ARHGAP5 2.82 (1.73-4.38) 3.71171E-05 0.481127 SEMA4B 5.67 (2.47-11.55) 7.26961E-05 0.508222 BMP6 21.51 (4.61-84.82) 0.000129025 0.532459 ARHGAP8 2.09 (1.44-2.94) 0.000147775 0.538345 SEMA4F 2.65 (1.59-4.2) 0.000177339 0.546349 LIMK2 2.01 (1.38-2.84) 0.000268991 0.565041 CLDN7 6.14 (2.33-13.83) 0.000294392 0.569165 PLCH1 2.89 (1.58-4.9) 0.000468941 0.590874 SEMA3A 1.96 (1.35-2.78) 0.000473086 0.591291 RAPGEF4 5.62 (2.14-12.56) 0.000477182 0.591701 EPHA7 1.75 (1.28-2.35) 0.000532366 0.596915 ROBO1 1.57 (1.2-2.03) 0.000985684 0.627028 WDR92 2 (1.31-2.94) 0.001134267 0.634072 NFATC3 18.8 (3.04-88.24) 0.001305353 0.641188 EPHA3 1.4 (1.14-1.72) 0.001443426 0.646323 SEMA3F 8.86 (2.16-27.24) 0.001902597 0.660605 ITGA3 1.34 (1.11-1.6) 0.002014978 0.663605 PARD3 3.77 (1.57-7.83) 0.002073143 0.665097 VAV2 1.9 (1.22-2.83) 0.003870616 0.698517 CLDN22 11.28 (1.99-43.91) 0.004112328 0.701829 KCNQ3 1.65 (1.15-2.29) 0.004775012 0.71005 NOX3 1.39 (1.1-1.75) 0.004875219 0.711198 ARHGEF15 1.62 (1.14-2.24) 0.005739783 0.720275 BDNF 1.25 (1.07-1.47) 0.005899809 0.721813

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

SRGAP2B 25.03 (2.09-218.75) 0.006398353 0.726362 SUCLG2 2.13 (1.22-3.48) 0.006607739 0.728174 SSH3 2.23 (1.2-3.84) 0.007653302 0.73648 NTNG2 2.01 (1.15-3.29) 0.008897961 0.74507 ESAM 1.32 (1.06-1.63) 0.012535174 0.764861 PXN 1.98 (1.06-3.4) 0.02099765 0.795268 SEMA6B 4.07 (1.05-11.36) 0.021408635 0.796424 VCAM1 10.73 (1.09-56.41) 0.021497596 0.796671 VCL 3.3 (1.03-8.19) 0.022411744 0.799158 SEMA6A 1.34 (1.03-1.71) 0.024105643 0.803518 LRRC4C 2.37 (1-4.84) 0.024989751 0.805677 NRP1 1.71 (1.01-2.72) 0.032389071 0.821307 MMP9 2.6 (0.92-5.91) 0.034361166 0.824887 SEMA4C 7.51 (0.8-35.35) 0.037438953 0.830094 CTNND1 7.51 (0.8-35.35) 0.037438953 0.830094 ACTN1 1.45 (0.99-2.04) 0.038665582 0.832053 ARPC1B 1.34 (0.99-1.78) 0.049749931 0.847423 CLDN16 37.51 (0.48-2864.71) 0.051281525 0.849277 NTRK2 3.01 (0.79-8.22) 0.051515852 0.849555 FGFR2 2.33 (0.83-5.27) 0.052125138 0.850275 OCLN 1.67 (0.96-2.73) 0.054940886 0.853494 PAPPA2 1.72 (0.95-2.89) 0.05756691 0.856352 MUS81 2.35 (0.74-5.74) 0.07055982 0.868822 PLXNA3 1.24 (0.96-1.57) 0.084562821 0.879914 PIK3R3 2.51 (0.66-6.78) 0.084914639 0.880168 CLDN11 3.05 (0.6-9.65) 0.08508261 0.880289 MME 1.41 (0.92-2.06) 0.08702862 0.881673 PLXNA2 1.14 (0.98-1.33) 0.090157746 0.883835 BOC 2.82 (0.56-8.87) 0.10052217 0.890485 SHC1 2.24 (0.59-6.04) 0.113210806 0.89773 ADAM23 1.63 (0.8-2.98) 0.117279008 0.899876 GLI3 1.22 (0.94-1.56) 0.118276276 0.90039 PLXNA4 1.26 (0.93-1.67) 0.127557545 0.904972 SEMA6D 2.06 (0.55-5.52) 0.140320349 0.910731 SEMA4D 1.11 (0.96-1.28) 0.141074092 0.911054 GNAS 1.23 (0.91-1.64) 0.153509184 0.916129 SLIT2 1.42 (0.8-2.35) 0.172077357 0.922941 GNAI3 5.36 (0.12-41.81) 0.189894993 0.928767 GNA14 1.58 (0.71-3.08) 0.197371627 0.931035 MLLT4 1.27 (0.82-1.87) 0.224625835 0.938558 CLDN3 1.65 (0.59-3.69) 0.280328985 0.951116 RYK 1.12 (0.91-1.36) 0.289866851 0.952968 SRGAP3 1.58 (0.57-3.53) 0.290360795 0.953062 EPHA1 1.15 (0.86-1.5) 0.307248395 0.956161 ALDH5A1 1.16 (0.85-1.55) 0.310731216 0.956774 CAMK2D 1.75 (0.2-6.72) 0.326970652 0.959522 MAPK13 1.27 (0.74-2.04) 0.342247422 0.961954

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

STK36 1.12 (0.87-1.41) 0.349337967 0.963036 ACTN4 1.2 (0.78-1.79) 0.37794465 0.967123 PAK6 1.2 (0.74-1.87) 0.392205363 0.969008 SEMA3E 1.08 (0.88-1.31) 0.449014465 0.975655 PRKAR2A 1.41 (0.28-4.28) 0.47831166 0.978614 SDC2 1.07 (0.8-1.4) 0.617834298 0.989353 GNAI1 1.07 (0.29-2.81) 0.790853296 0.99698 MMP15 1.05 (0.61-1.71) 0.799079966 0.997218 ITGA4 1.02 (0.41-2.14) 0.846145873 0.998382 PLXNC1 1.01 (0.46-1.95) 0.865022763 0.998758

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Table S5. Tops 10 and 25 significant genes and number of counts each gene have been found in the selected significant list CADD20 and Missense. Maximum value is 6 for genes appearing in all the lists.

TOP10 TOP25 Gene Top10 Gene Top25 DLC1 4 NTN4 6 DPYSL5 4 EPHA5 5 BMP1 4 ARHGAP5 5 PLXNB1 4 ARHGAP8 5 PLCE1 4 BMP1 5 EPHA5 3 IRS1 5 ARHGAP5 3 PLCE1 5 PLXND1 3 UNC5C 5 IRS1 3 PRKD3 4 UNC5C 3 DLC1 4 NTN4 2 DPYSL5 4 ARHGAP8 2 GAB1 4 GAB1 2 PLXNB1 4 STK36 2 PLXNA4 4 ROBO2 2 LRRC4 3 NOX3 2 ADAMTS1 3 PTK2 2 SEMA4F 3 PRKD3 1 STK36 3 EPHA7 1 RGS3 3 SEMA4F 1 PLXND1 3 NFATC3 1 EPHA7 2 CYBA 1 ESAM 2 PLXNC1 1 ROBO2 2 CLDN8 1 NOX3 2 SHC1 1 PTK2 2 SLIT2 1 VCL 2 FZD10 1 MLLT4 2 GLI3 1 ACTN1 2 EPHB1 1 PLXNB2 2 ENAH 1 SEMA4B 2 LIMK2 2 GLI3 2 ENAH 2 SEMA3A 1 SSH3 1 SUCLG2 1 ADAMTS9 1 NFATC3 1 CYBA 1 VAV3 1 GNAS 1 PLXNC1 1 PLXNA3 1 CLDN8 1

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

EPHA3 1 EPHB1 1 SEMA3C 1 SHC1 1 NCK1 1 ARPC1B 1 PIK3CA 1 ADAMTS4 1 KCNQ3 1 SLIT2 1 FZD10 1 WNT5B 1 SEMA6D 1 EPHA1 1 GLI1 1 SEMA6B 1 ICAM1 1 JAM2 1 BMP6 1 WDR92 0 RAPGEF4 0 RAF1 0 EPHB2 0 PAPPA2 0 SRGAP2 0 VAV2 0 CLDN7 0

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

Table S6. Parameter adjustments and outliers aminoacids for homolog protein model . and variant protein model of NTN4 using SWISS-MODEL builder.

NTN4 Homolog model Aminoacids MolProbity Score 1.33 Clash Score 0.61 (A381 ASP-A383 ARG) Ramachandran Favoured 93.74% Ramachandran Outliers 0.46% A102 PRO, A150 PHE Rotamer Outliers 1.91% A255 ASP, A126 TYR, A73 ARG, A455 CYS, A157 TYR, A286 PHE, A129 HIS C-Beta Deviations 3 A96 ASP, A150 PHE, A111 ASP Bad Bonds 0 / 3481 Bad Angles 23 / 4735 A129 HIS, A96 ASP, A327 ASN, (A203 PRO-A204 PRO), A365 ASN, (A282 ALA-A283 PRO), (A451 CYS-A452 ALA), A414 ASP, (A101 PHE-A102 PRO), A287 HIS, A290 HIS, A173 ASP, A384 ARG, A150 PHE, (A452 ALA-A453 GLY), (A136 SER-A137 PRO), A86 HIS, (A234 CYS-A235 PRO), A398 HIS, A303 HIS, A337 HIS, A89 HIS Cis Non-Proline 2 / 400 (A451 CYS-A452 ALA), (A452 ALA-A453 GLY) Cis Prolines 1 / 32 (A189 PHE-A190 PRO) Twisted Non-Proline 1 / 400 (A455 CYS-A456 ASP)

NTN4 Variant model Aminoacids MolProbity Score 1.27 Clash Score 0.62 Ramachandran Favoured 93.97% Ramachandran Outliers 0.46% A102 PRO, A150 PHE Rotamer Outliers 1.63% A255 ASP, A126 TYR, A455 CYS, A157 TYR, A286 PHE, A129 HIS C-Beta Deviations 2 A150 PHE, A111 ASP Bad Bonds 0 / 3488 Bad Angles 21 / 4746 A129 HIS, (A203 PRO-A204 PRO), A327 ASN, (A282 ALA-A283 PRO), (A451 CYS-A452 ALA), (A101 PHE-A102 PRO), A365 ASN, A287 HIS, A290 HIS, A414 ASP, A173 ASP, A150 PHE, A86 HIS, (A452 ALA-A453 GLY) (A136 SER-A137 PRO), A398 HIS, (A234 CYS-A235 PRO), A303 HIS, A89 HIS, A106 TRP Cis Non-Proline 2 / 400 (A451 CYS-A452 ALA), (A452 ALA-A453 GLY) Cis Prolines 1 / 32 (A189 PHE-A190 PRO)

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet

HIS

GLY),

Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159