Supplementary material J Med Genet

Supplemental figures and tables

Table S1. Summary of the trio and single proband-based experiment.

Sequencing Mean Percent Candidate Total NS/SS/I Family Individual output sequencing target de novo variantsa variantsa (in Gb) Depth (median) ≥ 10X SNV Trio 1 P1 dijex132 3,49 101.13 93.9 47848 14369 1 Mother dijex133 3,18 92.05 94.0 48178 14498 - Father dijex134 3,19 92.29 94.0 46912 14019 - Trio 2 P2 dijex135 3,23 93.38 94.0 48097 14526 1 Mother dijex136 3,63 105.11 94.4 48258 14480 - Father dijex137 3,32 96.19 94.0 47934 14657 - Trio 3 P3 dijex138 3,19 92.38 93.5 48365 14504 2 Mother dijex139 3 86.75 93.8 48229 14400 - Father dijex140 3,43 99.31 94.1 48035 14540 - Trio 4 P4 dijex141 3,42 98.89 94.5 47107 14126 2 Mother dijex142 3,69 106.78 94.4 47583 14365 - Father dijex143 3,38 97.81 94.3 48296 14667 - Trio 5 P5 dijex144 3,02 87.48 93.8 47648 14425 3 Mother dijex145 3,16 91.37 93.9 47284 14275 - Father dijex146 3,3 95.66 93.9 47964 14589 - Trio 6 P6 dijex147 3,51 101.74 94.1 48192 14568 3 Mother dijex148 3,15 91.20 93.8 48211 14638 - Father dijex149 3,11 90.12 93.8 47109 14178 - Trio 7 P7 dijex150 3,23 93.64 94.4 47648 14393 2 Mother dijex151 3,66 105.85 94.6 48040 14633 - Father dijex152 3,06 88.55 94.1 47950 14557 - Trio 8 P8 dijex153 3,18 91.99 94.0 48028 14633 4 Mother dijex154 3,42 99.05 94.0 48065 14472 - Father dijex155 3,43 99.40 94.0 48475 14635 - Trio 9 P9 dijex156 3,41 98.83 94.3 48682 14759 2 Mother dijex157 3,21 92.90 94.0 47604 14276 - Father dijex158 3,18 92.14 93.7 47682 14477 - Trio 10 P10 dijex159 2,85 82.49 93.6 47162 14193 1 Mother dijex160 3,02 87.53 93.7 47015 14266 - Father dijex161 3,66 105.82 94.0 47922 14530 - Trio 11 P11 dijex240 4,55 131.82 94.4 47777 14297 0 Mother dijex241 3,82 110.64 94.2 48415 14548 - Father dijex242 4,23 122.57 94.6 47923 14330 - Trio 12 P12 dijex244 2,9 84.10 93.7 47602 14441 2 Mother dijex245 3,44 99.63 94.1 47781 14564 - Father dijex246 2,85 82.45 93.7 48235 14841 - Trio 13 P13 dijex250 3,56 102.96 93.4 49688 15008 4 Mother dijex251 3,43 99.19 94.3 47888 14526 - Father dijex252 3,37 97.56 94.1 48549 14718 - Trio 14 P14 dijex253 3,02 87.49 93.8 47912 14322 3 Mother dijex254 4,27 123.50 94.6 48149 14513 - Father dijex255 3,12 90.42 94.0 48015 14327 - Trio 15 P15 dijex256 2,66 77.03 93.4 47958 14517 3 Mother dijex257 3,16 91.52 94.0 47898 14533 - Father dijex258 3,4 98.52 94.1 47962 14357 -

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Trio 16 P16 dijex374 2,89 83.66 94.0 55874 16557 0 Mother dijex376 3,01 87.24 94.2 57333 17154 - Father dijex375 3,01 87.21 94.2 56358 16861 - Trio 17 P17 dijex380 3,03 87.59 94.2 48224 14622 1 Mother dijex382 3,31 95.79 94.3 48945 14852 - Father dijex381 3,19 92.31 94.3 49171 15121 - Trio 18 P18 dijex377 3,07 89.01 94.3 47841 14520 2 Mother dijex379 3,02 87.42 94.2 48018 14594 - Father dijex378 3,25 94.09 94.3 48139 14539 - Trio 19 P19 dijex397 2,78 80.48 93.4 48341 14717 3 Mother dijex399 3,34 96.68 93.9 49299 15038 - Father dijex398 3,88 112.28 94.3 49618 15164 - Trio 20 P20 dijex265 3,35 97.00 94.3 48951 14806 1 Mother dijex393 3,29 95.25 93.7 47506 14352 - Father dijex392 3,29 95.15 93.9 49258 14968 - Trio 21 P21 dijex272 2,94 85.04 93.8 48799 14735 1 Mother dijex395 2,63 76.23 93.1 47352 14327 - Father dijex394 3,15 91.21 93.7 47966 14509 - Trio 22 P22 dijex383 3,24 93.68 94.1 48134 14494 1 Mother dijex385 3,13 90.63 94.3 49245 14972 - Father dijex384 3,31 95.70 94.5 49344 15058 - Trio 23 P23 dijex412 2,24 64.81 92.5 50721 15564 1 Mother dijex413 2,19 63.49 91.9 50642 15781 - Father dijex414 2,60 75.14 94.0 50727 15345 - Trio 24 P24 dijex758 3,52 101.96 96.5 49726 15181 2 Mother dijex759 3,63 105.22 96.4 50321 15479 - Father dijex760 3,69 106.72 96.3 49637 15195 - Trio 25 P25 dijex761 3,54 102.52 96.2 49847 15187 2 Mother dijex762 3,02 87.40 95.3 50109 15319 - Father dijex763 3,56 103.04 95.3 49315 15146 - Trio 26 P26 dijex838 5,34 154.69 96.7 52024 15681 2 Mother dijex839 3,29 95.16 95.6 51028 15515 - Father dijex840 3,14 90.84 95.4 50760 15436 - Trio 27 P27 dijex841 3,29 95.16 94.3 50051 15336 0 Mother dijex842 3,39 98.24 91.1 50603 15684 - Father dijex843 2,86 82.76 94.1 50754 15641 - Trio 28 P28 dijex879 4,67 135.12 95.9 48101 14483 2 Mother dijex880 2,96 85.68 94.5 48318 14761 - Father dijex881 2,89 83.62 94.4 47376 14402 - Trio 29 P29 dijex882 3,14 90.80 94.7 48538 14924 4 Mother dijex884 3,34 96.55 94.5 48458 14837 - Father dijex883 2,73 78.94 94.4 48003 14708 - Trio 30 P30 dijex905 3,15 91.09 94.6 48744 14886 2 Mother dijex906 3,07 88.93 94.5 48592 14859 - Father dijex907 3,32 96.25 94.7 48866 14898 - Trio 31 P31 dijex908 3,73 107.96 95.0 48714 14914 3 Mother dijex909 3,33 96.33 94.9 48419 14945 - Father dijex910 3,32 96.20 94.7 47989 14625 - Trio 32 P32 dijex911 3,27 94.72 94.8 48169 14623 1 Mother dijex912 3,44 99.66 95.0 48409 14746 - Father dijex913 3,34 96.71 94.6 47853 14556 - Trio 33 P33 dijex1277 3,29 95.18 95.8 58552 17553 1 + CNV Mother dijex1315 2,88 83.32 95.7 59246 17930 - Father dijex1316 3,32 96.22 96.3 59522 17894 -

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Solo 1 P34 dijex260 3,31 95.91 94.4 50938 15524 1 Solo 2 P35 dijex261 2,91 84.38 93.8 47796 14360 1 Solo 3 P36 dijex262 3,45 99.82 94.4 48560 14788 1 Solo 4 P37 dijex270 3,26 94.35 94.4 47250 14231 1 Solo 5 P38 dijex271 3,41 98.68 94.3 47740 14341 1 Solo 6 P39 dijex273 2,9 84.05 93.8 47212 14141 0 Solo 7 P40 dijex239 3,22 93.15 93.9 48447 14658 1 Solo 8 P41 dijex243 3,18 92.06 93.8 47813 14403 1 Solo 9 P42 dijex247 2,9 84.02 93.8 47995 14656 0 Solo 10 P43 dijex680 3,18 92.11 94.4 48882 14823 0 Solo 11 P44 dijex673 4,23 122.60 96.4 55694 16885 1 Solo 12 P45 dijex917 3,54 102.57 94.9 51197 15446 0 Solo 13 P46 dijex918 2,79 80.70 94.3 48151 14731 1 Solo 14 P47 dijex919 2,96 85.80 94.4 51849 15575 1 Solo 15 P48 dijex927 3,43 99.30 94.8 48267 14630 0 Solo 16 P49 dijex676 4,09 118.36 96.6 49411 15095 1 Solo 17 P50 dijex1278 3,61 104.42 96.1 49938 15168 0 Solo 18 P51 dijex1279 3,99 115.47 96.2 58548 17715 0 Solo 19 P52 dijex1292 3,91 113.10 96.3 49345 15119 1 Solo 20 P53 dijex1317 3,42 99.03 96.7 49705 14872 0 Solo 21 P54 dijex1383 4,68 135.44 96.9 50328 15152 0 Solo 22 P55 dijex1299 3,17 91.68 95.9 50286 15296 0 Solo 23 P56 dijex814 3,18 92.20 96.3 49657 15060 1 Solo 24 P57 dijex465 3,41 98.85 96.0 51337 15765 1 Solo 25 P58 dijex926 3,20 92,87 94,9 47414 14357 1 Solo 26 P59 dijex268 3,16 91.61 93.5 48320 14847 1 Solo 27 P60 dijex249 3,16 91.43 94.1 58020 17446 1 Solo 28 P61 dijex264 2,97 85.97 93.7 51780 15566 1 Solo 29 P62 dijex266 3,30 95.56 94.1 48566 14737 2 Solo 30 P63 dijex263 3,14 90.98 94.0 57077 17098 4 Solo 31 P64 dijex1509 3,36 97.48 96.6 60377 16569 1 Gb, gigabases; NS/SS/I, nonsynonymous changes, splice-site variants and insertions/deletions. aVariants that passed on the Genome Analysis Toolkit (GATK) hard-filtering parameters used for variant calling. Sequencing depth and coverage metrics were calculated using the GATK Depth of Coverage tool by considering only reads with mapping quality ≥ 20 and bases with base quality ≥ 20. SNV: Single Nucleotide Variant; CNV: Copy Number Variant.

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Table S2 : Genes with validated de novo non synonymous variants in the trios and the single-probands populations. Genes with pathogenic, likely pathogenic mutations and candidate genes appear in bold and strong candidate genes in bold with brackets.

Gene cDNA change aa change Trio # Trio 1 ZBTB20 NM_001164342.1:c.1862T>C p.Leu621Pro Dijex132 Trio 2 NFIB NM_001190737.1:c.376A>G p.Lys126Glu Dijex135 Trio 3 NEU3 NM_006656.5:c.316C>G p.Leu106Val Dijex138 RALGAPB NM_020336.2:c.457C>T p.Arg153Cys Trio 4 SLC6A1 NM_003042.3:c.1377C>A p.Ser459Arg Dijex141 ATXN2L NM_007245.3:c.944T>C p.Met315Thr CHD8 NM_001170629.1:c.3338delG p.Arg1113Leufs*41 Trio 5 HDLBP NM_001243900.1:c.2371C>G p.Arg791Gly Dijex144 CLDN11 NM_005602.5:c.93_104delGGTGACCTGCGG p.Val32_Gly35del NSD1 NM_022455.4:c.6020T>C p.Ile2007Thr Trio 6 METTL11B NM_001136107.1:c.13G>C p.Gly5Arg Dijex147 B3GALTL NM_194318.3:c.1353dup p.Asp452Glyfs*31 Trio 7 ARID1B NM_017519.2:c.5228_5231delAAAG p.Glu1743Alafs*9 Dijex150 COL6A3 NM_004369.3:c.432G>C p.Gln144His ZBTB46 NM_025224.3:c.1421A>G p.Tyr474Cys Trio 8 GLT8D2 NM_031302.3:c.785G>C p.Ser262Thr Dijex153 SPAG9 NM_001130527.2:c.650C>T p.Thr217Ile DSP NM_001008844.1:c.800A>C p.Asp267Ala Trio 9 NFIX NM_001271043.1:c.361A>G p.Lys121Glu Dijex156 SIDT NM_017699.2:c.2339G>A p.Arg780His Trio 10 TAF1 NM_004606.3:c.4549A>C p.Asn1517His Dijex159 Trio 11 - - - Dijex241 Trio 12 TAPBPL NM_018009.4:c.526A>C p.Asn176His Dijex244 RANBP10 NM_020850.1:c.1180G>A p.Ala394Thr NM_017519.2:c.5855T>C ARID1B p.Met1952Thr NM_015135.2:c.2008A>G Trio 13 NUP205 p.Thr670Ala NM_001144.5:c.1166G>A Dijex250 AMFR p.Arg389His NM_001076780.1:c.2747_2771delGACAGTCA PKD1L2 p.Gly916Aspfs*32 CTGAGCATAGACGTCAG ZEB2 NM_001171653.1:c.3026delA p.Lys1009Argfs*42 Trio 14 DKK3 NM_001018057.1:c.505C>A p.Gln169Lys Dijex253 PICALM NM_001008660.2:c.274-1G>A splice variant FBN2 NM_001999.3:c.4154T>C p.Leu1385Pro Trio 15* ATP1A1 NM_000701.7:c.2021C>G p.Thr674Ser Dijex256 WSCD2 NM_014653.2:c.628G>A p.Ala210Thr Trio 16 - - - Dijex374 Trio 17 SKIV2L2 NM_015360.4:c.1781A>G p.His594Arg Dijex380 Trio 18 EMILIN3 NM_052846.1:c.1645C>T p.Arg549Cys Dijex377 BEGAIN NM_001159531.1:c.1105G>A p.Gly369Arg Trio 19 ASXL3 NM_030632.1:c.3613G>T p.Glu1205*

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Dijex397 CIT NM_001206999.1:c.5047C>A p.Leu1683Met PNPLA6 NM_001166111.1:c.674C>T p.Pro225Leu Trio 20 TPCN2 NM_139075.3:c.1259C>T p.Pro420Leu Dijex265 Trio 21 NF2 NM_000268.3:c.535A>G p.Met179Val Dijex272 Trio 22 KCNB1 NM_004975.2:c.1240A>G p.Asn414Asp Dijex383 Trio 23 DSCAML1 NM_020693.2:c.3709G>A p.Val1237Ile Dijex412 Trio 24 ZBTB18 NM_006352.4:c.1274T>C p.Leu434Pro Dijex758 FKBP8 NM_012181.3:c.724G>A p.Ala242Thr Trio 25 CHD3 NM_005852.3:c.3477C>A p.Asn1159Lys Dijex761 FAM83H NM_198488.3:c.682G>A p.Val228Ile Trio 26 NFIX NM_002501.2:c.[346C>T;348G>A] p.Arg116* Dijex838 STK11 NM_000455.4:c.416_418delTGC p.Leu140del Trio 27 - - - Dijex841 Trio 28 ZEB2 NM_001171653.1:c.2995G>A p.Gly999Arg Dijex879 SYNGAP1 NM_006772.2:c.2047A>G p.Ile683Val MED13L NM_015335.4:c.3942_3943delCA p.Ile1315Glnfs*49 Trio 29 APOB NM_000384.2:c.619A>G p.Arg207Gly Dijex882 CREBBP NM_004380.2:c.1585A>G p.Met529Val

PAH NM_000277.1:c.1139C>T p.Thr380Met Trio 30 CDK13 NM_003718.3:c.2525A>G p.Asn842Ser Dijex905 CDH5 NM_001795.3:c.265G>A p.Val89Met DDX3X NM_001356.3:c.147delT p.Gly51Valfs*170 Trio 31 ARHGEF26 NM_001251962.1:c.999_1001delGAA p.Lys336del Dijex908 CNP NM_033133.4:c.1057C>T p.Arg353Trp Trio 32 FBXO11 NM_001190274.1:c.1042-1G>C splice variant Dijex911 Trio33 NSD1 CNV Dijex1277 CERS2 NM_181746.2:c.358C>T p.Arg120Cys

Solo # Solo 1 ATP1A1 NM_000701.7:c.998C>G p.Pro333Arg Dijex260 Solo 2 EHMT1 NM_024757.4:c.2608-1G>C splice variant Dijex261 Solo 3 NFIX NM_001271043.1:c.368G>A p.Arg123Gln Dijex262 Solo 4 SLC16A2 NM_006517.4:c.1390C>T p.Pro464Ser Dijex270 Solo 5** NUP205 NM_015135.2:c.595T>G p.Phe199Val Dijex271 Solo 6 - - - Dijex273 Solo 7 EHMT1 NM_001145527.1:c.1468C>T p.Arg490* Dijex239 Solo 8 SCN2A NM_001040142.1:c.5641G>T p.Glu1881* Dijex243

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Solo 9 - - - Dijex247 Solo 10*** - - - Dijex680 Solo 11 DLG4 NM_001128827.1:c.1705delG p.Glu569Serfs*4 Dijex673 Solo 12 - - Dijex917 Solo 13 DLG4 NM_001128827.1:c.1009_1016delTTTATCCT p.Phe337Glyfs*31 Dijex918 Solo 14 ARID1A NM_006015.4:c.4702C>T p.Pro1568Ser Dijex919 Solo 15 - - Dijex927 Solo 16 BCL11A NM_018014.3:c.193G>T p.Glu65* Dijex676 Solo17 - - - Dijex1278 Solo 18 - - - Dijex1279 Solo 19 Dijex1292*** - - - * Solo 20 - - - Dijex1317 Solo 21 - - - Dijex1383 Solo 22 - - - Dijex1299 Solo 23 CIC NM_015125.3:c.2974C>T p.Gln992* Dijex814 Solo 24 GABRA1 NM_000806.5:c.1207G>C p.Glu403Gln Dijex465 Solo 25 TBR1 NM_006593.2:c.896G>A p.Trp299* Dijex926 Solo 26 DLG4 NM_001128827.1:c.1534+2T>C splice variant Dijex268 Solo 27, - - - Dijex249 Solo 28, - - - Dijex264 Solo 29, - - - Dijex266 Solo 30, - - - Dijex263 Solo 31 [SATB1] NM_001195470.1:c.1004_1005delGA p.Arg335Thrfs*20 Dijex1509 * Also carries a TAF1 mutation inherited from the mother (see table S2) ** Also carries a truncating NSD1 mutation inherited from his symptomatic mother (see table S2) *** Carries a truncating ATRX mutation inherited from his mother (see table S2) **** Carries a missense USP9X inherited from his asymptomatic mother (see table S2)

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Table S3. Allele frequency and bioinformatics predictions of the pathogenicity of the mutation sites associated with marfanoid habitus and in 125,748 exomes from the gnomAD data set.

MAF MAF Gene cDNA change Polyphen GERP Grantham CADD dbSNP ID ClinVar status pLI (ExAC) (gnomAD) NM_001251962.1: ARHGEF26 - 5.400 - - rs535601495 - 0.000108 0.000105 0.00 c.999_1001delGAA ARID1A NM_006015.4: c.4702C>T 0.828 4.380 74 22.5 rs113718290 - 0.000050 0.000076 1.00 NM_017519.2: ARID1B - 5.050 ------1.00 c.5228_5231delAAAG NM_017519.2: ARID1B 0.959 4.960 81 25.8 - - - - 1.00 c.5855T>C NM_030632.1: ASXL3 - 5.050 - 38 - - - - 1.00 c.3613G>T NM_000701.7: ATP1A1 0 5.150 58 22.4 - - - - 1.00 c.2021C>G NM_000701.7: ATP1A1 1 4.870 103 22.3 - - - - 1.00 c.998C>G NM_000489.3: ATRX - 3.830 - 36 rs122445108 Pathogenic - - 1.00 c.109C>T NM_018014.3: BCL11A - 5.780 - 37 - Likely Pathogenic - - 0.83 c.193G>T NM_021946.4: BCORL1 0.234 5.800 21 22.5 - - - - 0.98 c.1288A>G NM_003718.3: CDK13 1 4.620 46 24.7 - Pathogenic - - 0.75 c.2525A>G NM_005852.3: Pathogenic/Likely CHD3 0.822 1.480 94 22.2 - - - 1.00 c.3477C>A Pathogenic CHD8 NM_001170629.1: c.3338delG - 5.420 56 - - - - - 1.00 NM_015125.3: CIC - 5.140 - 15.13 - Pathogenic - - 1.00 c.2974C>T CNP NM_033133.4: c.1057C>T 0.992 2.160 101 21.6 rs376643712 - 0.000058 0.000037 0.89 NM_004380.2: CREBBP 0.069 4.390 21 18.65 rs747187975 - 0.000008 0.000008 1.00 c.1585A>G NM_001356.3: DDX3X - 2.520 ------1.00 c.147delT NM_001128827.1: DLG4 - 4.090 ------1.00 c.1705delG NM_001128827.1: DLG4 - 5.280 ------1.00 c.1009_1016delTTTATCCT NM_001128827.1: DLG4 - 5.200 - 27.8 - - - - 1.00 c.1534+2T>C

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NM_024757.4: EHMT1 - 5.490 - 25.9 - - - - 1.00 c.2608-1G>C NM_024757.4: EHMT1 - 5.560 - 19.45 - - - - 1.00 c.1468C>T NM_052846.1: EMILIN3 0.968 4.560 180 20.2 - - - 0.000008 0.00 c.1645C>T NM_001999.3: FBN2 0.997 4.900 98 25.0 - - - - 1.00 c.4154T>C FBXO11 NM_001190274.1:c.1042-1G>C - 5.970 - 31 - - - - 1.00 NM_000806.5: Uncertain GABRA1 0.049 4.440 29 22.5 rs775157869 0.000008 0.000008 0.96 c.1207G>C significance NM_000833.3: Uncertain GRIN2A 0.87 4.380 45 22.2 - 0.000049 0.000041 1.00 c.3120G>C significance NM_004975.2: KCNB1 0.949 6.070 23 25.8 - - - - 0.98 c.1240A>G NM_001008537.2: KIAA2022 0.181 5.270 94 22.4 - - - - 0.95 c.3428A>G NM_015335.4: MED13L - 5.960 ------1.00 c.3942_3943delCA NM_001190737.1: NFIB 0.979 5.710 56 16.24 - - - - 0.99 c.376A>G NM_001271043.1: NFIX 0.999 4.230 56 17.68 - - - - 0.99 c.361A>G NM_001271043.1: NFIX 1 5.260 43 20.6 - - - - 0.99 c.368G>A NFIX NM_001271043.1: c.361A>G 0.999 4.230 56 17.68 - - - - 0.99 NM_022455.4: NSD1 1 5.420 89 29.8 - Likely pathogenic - - 1.00 c.6020T>C NM_022455.4: NSD1 - 3.630 ------1.00 c.7449delT NM_015135.2: NUP205 0.449 5.360 58 19.48 - - 0.000033 0.000045 1.00 c.2008A>G NM_015135.2: NUP205 0.178 5.610 50 23.3 - - - 0.000008 1.00 c.595T>G Likely NM_005859.3: PURA 0.131 2.620 27 17.03 - benign/Uncertain - 0.000242 0.85 c.40G>C significance NM_001195470.1: SATB1 - 5.750 ------0.86 c.1004_1005delGA SCN2A NM_001040143.1: c.5641G>T 0.999 5.530 - 50 - - - - 1.00 NM_006517.4: SLC16A2 1 5.440 74 29.9 - - - 0.000008 0.93 c.1390C>T

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NM_003042.3: SLC6A1 1 5.490 110 32 - Likely pathogenic - - 1.00 c.1377C>A NM_006772.2: SYNGAP1 0.313 4.940 29 22.3 rs147668681 - - - 1.00 c.2047A>G NM_138923.2: TAF1 1 4.650 68 21.6 - - - - 1.00 c.4486A>C TAF1 NM_004606.3:c.4190G>A 0.999 4.080 43 25.0 - - 0.000008 0,000006 1.00 NM_006593.2: TBR1 - 5.070 - 22.4 - - - - 0.99 c.896G>A NM_001135599.2: Uncertain TGFB2 1 5.09 29 25.8 0.000025 0.000025 0.99 c.484G>A significance NM_015542.2: UPF2 0.361 5.440 29 19.55 - - - - 1.00 c.358C>G NM_001039590.2 : USP9X 0.672 5.800 98 20.8 rs372517093 - 0.000008 0.000011 1.00 c.3410C>T NM_006352.4: ZBTB18 0.999 5.680 98 16.31 - - - - 0.97 c.1274T>C NM_001164342.1: ZBTB20 0.999 6.170 98 29.1 - - - - 0.98 c.1862T>C NM_025224.3: ZBTB46 1 4.1440 194 18.77 - - - - 0.81 c.1421A>G NM_014795.3: ZEB2 - 5.870 ------1.00 c.3098delA NM_001171653.1: ZEB2 1 5.940 125 34 - - - - 1.00 c.2995G>A

Ref, reference allele; alt, alternative allele; MAF: Minimum allele frequency; pLI: probability of loss of function intolerance. The nomenclature of mutations is based on RefSeq accession number NM_181523.2. The gnomAD data set consists of deep coverage whole exome data from 125,748 subjects (see Web Resources). GERP : Genomic Evolutionary Rate Profiling; MAF: Minor Allele frequency; pLI: probability that a gene is intolerant to a loss of function mutation

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Table S4. Results from simulating the number of genes with two or more de DNM from 60 randomly selected SSC unaffected sibling trios over 500,000 trials.

Number of genes with two mutations in Number of groups of 60 individuals with the same gene the event 0 438,949 1 57,220 2 3,634 3 194 4 3 5 0 6 0 7 0 8 0

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Table S5. Estimated risk of recurrence of DNM in more than one patient in our population of 60 probands with parental data using a previously reported model and rates, with uncorrected simulated p-values [1].

Gene De novo missense De novo severe Total P# variants variants

ARID1B 1 1 2 3.84 x 10-6 ATP1A1 2 0 2 1.28 x 10-6 DLG4 0 3 3 <2.0 x 10-8 EHMT1 0 2 2 1.2 x 10-7 NFIX 2 0 2 <2.0 x 10-8 NUP205 2 0 2 2.18 x 10-5 ZEB2 1 1 2 1.8 x 10-7 X obs # For gene i, we calculated the probability of observing i or more of any -altering Y obs events, and among them i or more severe events, from 50 million simulations. Note: NSD1 and TAF1 were not included in the analysis since the mutation was inherited from an affected parent in one patient for NSD1, and inherited from the mother in TAF1

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Supplemental note: case reports Clinical information of patients with pathogenic or likely pathogenic variants in known genes compatible with the patient phenotype (alphabetical order)

ARID1B Trio 7 The proband had uneventful family history. His neonatal measurements were not known. He had surgery for . He had mild ID and behavioral abnormalities including anxiety, hyperactivity and psychotic manifestations. His skeletal features included long and thin habitus, pectus abnormalities, , and dolichostenomelia (systemic score of 4). His adult size was 164.5 cm, weight 50 kg and OFC 54 cm. He had aortic bicuspid valve, myopia and strabismus. No diagnosis was raised. After the discovery of a de novo truncating ARID1B variant, reverse phenotyping did find some features of the Coffin-Siris spectrum, including , low frontal hairline, thick eyebrows, long eyelashes, narrow palpebral fissures, large mouth and low-set ears. This result confirms the high clinical variability associated to the ARID1B spectrum [2], and the frequent association between ARID1B and ID [3].

Trio 13 The proband was the unique child of an European ancestry father and an Asian mother. She was born at term with a length of 49 cm, a weight of 2900 g and an OFC of 34 cm. She could walk independently at age 20 months. She developed seizures at age 8, with anxiety and mild ID. At age 15 years, she presented left hemiplegia secondary to transitory ischemic stroke. She had normal measurements (size 159 cm, weight 49 kg, OFC 56 cm) but had long and thin habitus with dolichostenomelia ( span 170 cm), arachnodactyly with positive thumb and wrist sign, scoliosis, hyperlaxity, flat feet, and highly arched palate systemic score of 7). She had normal heart and eye investigations. After the discovery of a de novo ARID1B missense variant, reverse phenotyping did find some features of the ARID1B spectrum, including low frontal hairline, tick eyebrows, long eyelashes, narrow palpebral fissures, large mouth with thin superior lip and thick inferior lip and low-set ears. A NUP205 variant was also found de novo.

ATP1A1 Solo 1

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The proband had 6 unaffected siblings. The parents were consanguineous. She had mild ID with normal behavior. Her adult height was 176 cm, her weight 58 kg and her OFC 55 cm. She had a long and thin habitus, , scoliosis, dolichostenomelia and arachnodactyly. She had a long hypomimic face with a prominent nasal root, small chin, and highly arched palate with crowded teeth. She had striae and mitral valve prolapse (systemic score of 9). ATP1A1 has recently been reported in three patients with generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting [4]. There was no hypomagnesemia was not searched and seizures were not reported in solo 1. Marfanoid features were not described in the patient reported by Schlingmann, but they are still young (4, 6 and 10 years). The ATP1A gene family encode subunits of a Na+, K+-ATPase ion pump. ATP1A2 and ATP1A3 are already known contributors to neurological disorders [5]. Bioinformatic characteristics of the variant were convincing, and a collaboration was set up with the Schlingmann team with modeling in favor of the pathogenicity of the variant (data not shown) [4]. Genematcher permitted contact with other clinicians that found ATP1A1 variant with non-specific NNDs (personal communication).

ASXL3 Trio 19 This 20-year-old female had a healthy sister. She had normal birth measurements but an OFC of 37 cm. She was diagnosed with club hands at birth. She had severe feeding difficulties with vomiting in the first months of life. She had severe motor delay, since she sat at age 4 years and walked independently at age 6 years. She said only few words. She was in a school for special needs. She had epilepsy, developed anxious manifestations with hyperactivity and sleeping disorders. She also had self-injuries with obsessive compulsive disorder. At last examination, her size was 155 cm, weight was 38 kg and OFC 55 cm. She had a thin habitus, , scoliosis since the age of 5 years, dolichostenomelia, arachnodactyly with long feet, limited extension of elbows with , flat feet and highly arched palate. She also displayed severe dysmorphic features with a long face, little facial expression with an open mouth appearance, temporal narrowing, arched eyebrows, down-slanting palpebral fissures, strabism, prominent nasal bridge, small alae nasi, anteverted nares, prominent columella, malar hypoplasia, microretrognathia, teeth malposition (systemic score of 10). Puberty was normal. Cardiac and ophthalmologic evaluations were normal. CT scan revealed a thin corpus callosum with mild white matter volume loss.

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Reverse phenotyping allowed the diagnosis of Bainbridge-Ropers syndrome, although marfanoid syndromes with ID has not been discussed as a differential diagnosis of this entity [6]. This patient was previously reported in Kuechler et al., 2017 [7].

ATRX Solo 10 The proband had a healthy sister. There was no family history of similar cases. The pregnancy and delivery were uneventful, with normal measurements at birth. He sat at 15 months and walked at 24 months. Clinical examination at age 32 years revealed a long and thin habitus with a height at 195 cm (+2.5 SD), a weight of 73 kg (mean) and an OFC of 54.5 cm (mean). Facial features included downslanting palpebral fissures with deep-set eyes, strabismus, superior periorbital oedema, a prominent nose, and narrow, low-set, posteriorly rotated ears. He had camptodactyly, , scoliosis and dolichostenomelia (systemic score of 3). He had moderate ID and behavioral abnormalities. He had normal heart survey. The ATRX mutation was found to be inherited from the mother. The mutation had already been reported in the literature. Reverse phenotyping did not find distinctive clinical features of ATRX syndrome, including characteristic tented vermilion of the upper lip, and thick or everted vermilion of the lower lip, or telecanthus. Investigations have been performed in order to identify alpha-thalassemia. Other families have been diagnosed by exome sequencing, and presenting with non-specific ID with indistinctive facial features [8].

BCL11A Solo 17 This male patient has been reported in Dias et al., 2016 (patient 9) [9], and participated in the identification of BCL11A as a new disease-causing gene. The patient had two healthy brothers and was born from unrelated parents. He had moderate ID without . He sat independently at 12 months, walked independently and said his first words at 36 months. He did not behavior anomalies nor sleep disturbance. At last examination at age 10 years, he measured 144 cm and had an arm span of 154 cm. He had thin habitus, epicanthus, strabismus, flat midface, thin upper lip, everted lower lip, high nasal bridge, micro/retrognathia, teeth anomalies, joint hypermobility, and pectus excavatum (systemic score of 3). He had mild myopia.

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MRI revealed mild hypoplasia of the corpus callosum. Standard genetic investigations were normal. After identification of a BCL11A variant, the foetal hemoglobin was found 8.6%.

CDK13 Trio 30 The proband was the unique child from non-consanguineous parents. The mother had a history of a first trimester miscarriage. The patient was born at 38.5 WG by caesarean section because of fetal bradycardia, meconial amniotic fluid, and Apgar score of 3 at 1 minute and 7 at 5 minutes. Birth length was 46 cm, weight 2400g, and OFC 32cm. She had early closure of fontanelles at 3.5 months. At 6 years of age, she still had growth delay with a height of 109 cm (-1SD), a weight of 14.6 kg (-2SD), and an OFC of 49cm (-1SD). She had axial , , strabismus, , small nose, long philtrum, bilateral epicanthus, , small mouth with down- slanting corners and thin lips, asymmetrical low set ears and thick helix. She had marfanoid habitus, long fingers and and generalized hyperlaxity (systemic score of 3). Hands and feet showed simian and deep creases with fetal pads. She had achromic spots on the abdominal region and angioma on the large forehead. He had poor language with very few words and communicated using Makaton. He had attention disorder, akinetic gestalt but good comprehension. He had sleep disorders with frequent nightmares. Cardiac and renal ultrasound were normal, cerebral MRI showed a small posterior hole at the occipito-cervical junction and asymmetrical temporal horns. A skin biopsy was realized and electronic microscopy showed normal elastic fibers, collagen fibers with hair pin structure, myelinated nerve fibers with thickened sheath. Array-CGH was normal. Reverse phenotyping showed dysmorphic features in favor of the implication of CDK13 in the patient phenotype. Recently, it has been shown that cardiac defects are not always described in patients with CDK13 variants [10].

CHD3 Trio 25 This patient was included in the paper describing missense mutations of CHD3 as a cause of a novel syndromic developmental disorder [11]. This girl was the first and only child of non-consanguineous parents of European ancestries. There was no family history of neurological or neuromuscular disorders. She was delivered at

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30 WG by normal vaginal delivery following an uneventful pregnancy. Weight at birth was 1475 g (-1.5 SD); length 40 cm (-1 SD) and head circumference 29 cm (mean). She was hospitalized until 2.5 months for respiratory distress, feeding difficulties and hypotonia. She had global developmental delay without any period of regression. She sat with support at 14 months and without support at 4 years, crawled at 3 years, walked at 5 years. Her speech development was also markedly delayed. She was babbling at around 2 years and did not have any recognizable words before the age of 7. She was noted to have a happy behaviour but with a poor visual contact. She did not suffer from seizures. At last examination, she was noted to have dysmorphic facial features, including a high anterior hairline, , anteroposterior elongation of the skull, frontal bossing, flat midface, hypertelorism, epicanthus, wide mouth, highly arched palate, low set ears, long and thin habitus, thin hands, pectus chest deformity, pes planus, joint hypermobility, hypertrichosis and global hypotonia (systemic score of 3). All growth parameters were normal. Her PC was at +2SD. Routine laboratory tests, screening for serum amino acids, urinary organic acid level, echocardiography, abdominal echography and MRI were normal. Karyotype analysis and CGH-array were negative. Hearing tests were also normal and ophthalmologic exams showed squint.

CHD8 Trio 5 The proband had an unaffected brother. He was born at 34 WG with tall stature (length 50 cm, weight 2875 g, OFC 33 cm). He could walk at 26 months and did not develop speech. He had frequent stereotypies. At last examination at 5.5 years, his size was 128 cm (+3SD), his weight was 21.4 cm (normal) and OFC 54 cm (+2 SD). Facial features included triangular face with large forehead, high arched interrupted eyebrows and smooth philtrum He had long and thin habitus, pectus excavatum, hyperlaxity, scoliosis, arachnodactyly, flat feet valgus, highly arched palate and amyotrophia (systemic score of 6). His heart and eye survey revealed an aorta at the upper normal limit, aortic valve prolapse, strabism and myopia. His brain MRI was normal. Direct sequencing and search for large rearrangement in NSD1 was negative. Methylation analysis of the 15q11–q13 region was normal. Reverse phenotyping was difficult in the presence of limited clinical description associating autistic features and [1,12].

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CIC Solo 23 This patient has been reported in Lu et al., 2017 [13] (patient 4), and participated in the identification of CIC as a new disease-causing gene. This 15-year-old Caucasian boy had a diagnosis of oligohydramnios during pregnancy. He was born full term, with normal measurements. His early milestones were normal and he walked at 13 months. He had learning difficulties at school and attended a special school from 11 years of age. At 14 years old, he could only read simple sentences with little understanding, and write his name. He had behavioral issues described as autistic features (hyperactivity, stereotypic movements, and anxiety). He had an electroencephalogram when he was five years, that showed non-specific abnormal pattern. His brain MRI showed non-specific white matter signal anomalies. At last examination, his weight was 62 kg (+2 SD), height was 184 cm (+2.5 SD), and head circumference was 54 cm (+1 SD). He had a marfanoid habitus including scoliosis, arachnodactyly, flat feet and slender built (systemic score of 5). He had inappropriate laughing episodes.

DDX3X Trio 31 This female patient is the third child of healthy parents from Chinese origin. She was born at 32 weeks of gestation with a weight of 2220 g, length 45 cm, occipitofrontal circumference 32 cm. Apgar scores were 6 and 9 at 1 and 5 minutes, respectively. She had mild respiratory distress requiring oxygenotherapy and transient hypocalcemia on the second day of life. Global developmental delay and axial hypotonia had been noticed since the first months of life. She sat at 12 months, walked at 24 months and spoke her first words at 3 years. She had a scoliosis diagnosed at the age 3 years. Later on, marfanoid habitus, arachnodactyly and highly arched palate were also noticed (systemic score of 4). Echocardiography was normal. At age 15 years, she had moderate to severe ID, normal neurological examination and growth parameters (height 151 cm (-1.5 SD), weight 43 kg (-1.5 SD), OFC 56.5 cm (+1.5 SD). Marfanoid habitus has not previously been described in patients with DDX3X gene reported to date [14].

DLG4 (these 3 patients have been reported in Moutton 2018) [15]. Solo 11

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Patient 3 was born to non-consanguineous parents after an uneventful pregnancy and birth. He had no particular developmental delay since he sat unsupported at age 6 months, walked alone at age 12 months, said his first words at age 18 months and his first sentences at age 36 months. He learned to read and write but attended special education and a private professional high school to obtain a professional high school diploma. He worked in a protected environment in the era of graphics. IQ performed at age 17 years was assessed at 56. He was described as anxious. At last examination at age 23 years, the height was 173 cm consistent with his target height, long face, highly arched palate with nasal voice, marked dolichostenomelia, arachnodactyly, some degree of hyperlaxity, striae and mild unilateral nystagmus. He underwent 2 surgeries for umbilical hernia and was followed for mild scoliosis from age 14 years onwards (systemic score of 7). Cardiac ultrasound, ophthalmological examination, brain MRI were normal. Karyotyping, search for fragile X syndrome, array-CGH and homocysteine dosage were not contributive. The parents did not exhibit a marfanoid habitus. The father was 178 cm, 78 kg and 58 cm OFC; the mother was 158 cm, 55 kg and 57 cm OFC.

Solo 13 Patient was born to non-consanguineous parents, family history was not informative. Pregnancy and birth were uneventful, birth parameters were within normal range. He presented with transitory neonatal jaundice. At age 6 months, an axial hypotonia was noted. He could walk unassisted at age 18 months and spoke his first word at age 24 months and his first sentences at age 3 years ½. Audiometry was normal. He could learn his 2 maternal languages with comprehensive difficulties in both of them. He was educated in a special need school from age 6 years onwards. He required ritualized lifestyle but other behaviour was not consistent for ASD. His autonomy was limited and he needed verbal assistance to perform the main daily activities. At age 17 years, his scholar abilities were assessed to be equivalent to a 7-8-year-old child with possibilities to read and write. He was followed for myopia prevailing on the left side, scoliosis and was treated for urticaria. He did not experience seizures. Examination revealed mild pyramidal signs, static ataxia, buccal apraxia, dystonia, syncinesia at the test of elbow rapid alternating movements, decreased hand muscle strength, clumsiness, strabismus, highly arched palate, long and thin fingers and pectus excavatum (systemic score of 3). He had a dental articular disorder but this finding was present in his mother and his half-sister.

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Spine X-rays performed at age 17 years revealed a 14° T1-T6 left convexity and 12° T11-L3 right convexity scoliosis with moderate vertebrae rotation. The different brain MRI performed at age 9 months, 3 years and 16 years showed mild left occipital subcortical atrophy with a very mild FLAIR white matter hyperintensities and the last control also found a mild vermis atrophy. Cardiac ultrasound showed mild aortic ring dilation (23-24 mm) with no increased aortic diameters at the other sites of measure. Karyotyping, array-CGH, FMR1 CGG repeat count, transferrin electrophoresis and homocysteine dosage were normal. At last examination at age 21 years, growth charts indicated height on +1.5SD (standard deviation) (target size -1SD), weight was average and OFC was +0.5SD. Arm span to height ratio was 1.01. The parents did not display marfanoid features, the father measured 172 cm, the mother 157 cm, and the paternal grandfather 186 cm.

Solo 26 Patient was born to non-consanguineous parents after an uneventful pregnancy and birth but decreased active fetal movements were noted. Measurements were in normal ranges (2850 g, 48 cm, OFC not available). Developmental delay was noted soon during infancy since he stood his head at 4-5 months, sat unsupported at 12 months and walked alone at 24 months of age. Language skills were highly altered and the neuropsychological evaluation performed at age 12 years was not possible, even using nonverbal tests suggesting a moderate to severe ID. He did not reach any reading or writing abilities. He was also described with relationship problems and had stereotyped activities. The diagnosis of autism spectrum disorder was made. He suffered from seizures starting at age 14 years. At last examination at age 35 years, he was 183 cm height (+1.8SD, target height +1.3SD), 70 kg weight and 56 cm OFC. Arm span was 190 cm and the ratio to the height was 1.04. In addition to classical marfanoid habitus features, he exhibited long face, telecanthus, short philtrum, thin vermillion of upper lip, long 2nd , increased space between 1st and 2nd toes, ulna valga, lumbar hyperlordosis, delayed puberty (systemic score of 3). He followed a special education and attended an occupational institution as an adult. He had limited autonomy and needed help including to dress and get washed. He was treated by olanzapine and sodium valproate. Investigations included ophthalmological evaluation showing mild myopia, limited convergent and vertical gaze movements. Cardiac ultrasound showed floppy mitral valve. Neurological examination identified tandem gait difficulties without dysmetria but fine motor anomalies, strabismus and brisk reflexes. Brain MRI performed at age 25 years showed cortical subcortical

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atrophy and mild ventricle enlargement prevailing on the left side. Spectro-MRI showed a slight decrease in N-acetyl aspartate. The tractography identified a mild increase of right cingulum volume. Karyotyping, search for fragile X syndrome, array-CGH and homocysteine dosage were not contributive. Familial history was unremarkable and the parents did not manifest with marfanoid features. The mother was 168 cm height and 56 cm OFC. The father was estimated to measure 185 cm.

EHMT1 Solo 2 The proband had a healthy brother. Her measurements at birth were 48 cm for length, 3050 g for weight and 32 cm for OFC. She was early diagnosed with congenital glaucoma. She walked at 18 months, and had severe speech difficulties. She developed seizures, as well as psychotic behavior with severe anxiety. At last examination in adulthood, she only associated words, and had incomplete autonomy with severe ID. She could eat alone but could not do her toilet alone or walk outside for activities. Her adult height is 181 cm (>+3 SD), weight was 70 kg. Her skeletal features included long and thin habitus, dolichostenomelia, scoliosis that necessitated corset treatment, arachnodactyly, flat feet and highly arched palate (systemic score of 6). She had myopia. Cerebral CT scan and cardiac ultrasound were normal. After the finding of a splicing EHMT1 variant, her facial features were carefully analysed. She had coarse face, thick eyebrows, mid face hypoplasia, with everted lower lip. However, she did not have hypertelorism, synophrys, short nose with upturned nares, protruding tongue and obesity. She had no sleep disturbances. Retrospective diagnosis of Kleefstra syndrome remained difficult although compatible. Tall stature has been reported in the literature in a fourth of the patients (6/22 cases) [16].

Solo 7 The proband had 2 unaffected siblings and the parents had two miscarriages. Measurements at birth were 49 cm for length, 3.6 kg for weight and 33.2 cm for OFC. He had severe psychomotor retardation with independent walk at age 3 years and absent speech. He had to be orientated early in a school for special needs. He had severe ID but no epilepsy. He did not develop epilepsy but had severe anxiety and phobias. At last examination at the age of 27 years, his height was 190 cm (+2.5 SD), weight 66 kg and OFC 54 cm (-2.5 SD). He had long and thin habitus, pectus excavatum, scoliosis,

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arachnodactyly, long feet (shoe size 45), hyperlaxity with limited extension of elbows, flat feet, and highly arched palate. He had surgery for bilateral inguinal hernia. He had facial hypomimia with salivar incontinence. Ophthalmological examination revealed hypermetropia, cerebral CT scan was normal. Reverse phenotyping after the finding of an EHMT1 mutation permitted to delineate facial features in common with Kleefstra syndrome, including coarse face, microcephaly, synophrys with thick eyebrows, down-slanting palpebral fissures, mid face hypoplasia, short nose, short philtrum, everted lower lip and a mouth with down turned corners and protruding tongue.

FBN2 Trio 15 The proband was the second children of healthy parents. He had a brother with learning disabilities and long and thin habitus without any other skeletal features reminiscent of and without aortic dilatation. He had normal measurements at birth and ventricular septal defect was evidenced at that time. Follow up revealed dilated aorta at the sinus of valsalva at age 2.5 years (22 mm, +3SD). He also had long and thin habitus, pectus excavatum, dolichostenomelia, arachnodactyly with positive thumb and wrist sign, flat feet, hyperlaxity and highly arched palate (systemic score of 7). At last examination at age 10 years, the initial diagnosis of marfanoid habitus with ID was reclassified to learning disabilities. He measured 147 cm with an arm span of 158 cm, and keep a severe long and thin habitus. He was in normal school but necessitated some extra help. He had surgery of bilateral unstable patella, wore glasses for myopia, and was treated by Propanolol for stable aortic dilatation. He also carries a de novo FBN2 mutation that is predicted to be likely pathogeneous and that might contribute to his MH. Like his brother, he also carries a TAF1 variant inherited from her mother who had a biased X-inactivation (97:3). This variant is of unknown significance. This variant had been reported once in GnomAD, and had not been found in the maternal grand- father and the maternal uncle. However, he had no dystonia. A de novo ATP1A1 variant of unknown significance was also found, with magnesium level at the lower limit.

FBXO11 Trio 32 This patient has been reported in Gregor et al., 2018 (patient 10) [17], and participated in the identification of FBXO11 as a new disease-causing gene.

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He was born at term with birth weight of 3900 g, and a length of 52 cm. He walked at age 24 months, was diagnosed with mild-moderate ID, and suffered from hyperactivity, mood disorder. At last examination at age 10 years, size was 167.5 cm (+4 SD), weight 59 kg (+2 SD), OFC 53.5 cm (mean). He had a long face, epicanthic folds, retrognathia, mandibular hypoplasia, flat feet, , joint hypermobility, marfanoid habitus, cubitus valgus, striae. He also had hypermetropia, strabismus and aortic dilatation. This association raised the question of Shprintzen-Goldberg syndrome.

KCNB1 Trio 22 This 17-year-old female was seen in the genetic clinic for the association of ID, epilepsy, behavioral abnormalities that necessitated treatment and dysmorphic features. She had poor speech. She wore braces for severe scoliosis. At last clinical examination, she has a long and thin habitus with a size of 171 cm contrasting with an arm span of 186.5 cm, she weighed 55 kg and her OFC was 53 cm. She had arachnodactyly, hyperlaxity (systemic score of 5). She had dysmorphic features including a long face, short philtrum, thick lips, highly arched palate, teeth malposition with prominent incisors. She had hyporeflexia. Heart survey was normal. The presence of severe ID and epilepsy is compatible with the spectrum of KCNB1 mutations although the absence of specific features limited the reverse phenotyping approach [18]. There was no data in favor of an association between the MH and the KCNB1 mutation, and further clinical description would be necessary.

MED13L Trio 29 The proband had a healthy older sister. Parents are unrelated with no personal or family history. The father's height was 190 cm and mother's height 171 cm. The father was 40-year-old and the mother 28-year-old at time of birth. The pregnancy was uneventful until 35 WG, when the diagnosis of fetal distress was made justifying caesarian section. Birth weight was 2290 gr; birth length 45 cm, birth OFC 34 cm. Because of severe respiratory distress, the child was admitted to the neonatal intensive care unit, and a was diagnosed in the presence of micrognatia and posterior cleft palate. At the age of 40 days, he underwent

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tracheostomy that was closed after 18 months. Right inguinal hernia and pyloric stenosis were surgically corrected. Psychomotor development was clearly delayed. He sat without support at 3 years of age, he walked unaided at 4 years, he said individual words at 4 years and full sentences at 8 years. Moderate ID was assessed. During childhood, slender habitus, hyperlaxity, pectus excavatum and progressive lumbar scoliosis became evident. Long hands and long slender fingers were noticed, as well as bilateral camptodactyly of 3-4-5 toes (systemic score of 6). Myopia was diagnosed at the age of 8 yrs. Puberty began at the age of 14 years. Height was between the 10th and the 25th centile. Brain MRI revealed areas of polymicrogyria. Array-CGH was normal. Marfanoid habitus has not been reported in classical clinical descriptions of patients with MED13L variants [19]. This patient is part of the Smol et al. paper [20].

NFIB Trio 2 This patient is part of the paper describing the first series of patients with ID and macrocephaly associated with NFIB variants and CNVs [21]. The proband had a healthy sister. He was born at term with macrocephaly (birth length 50 cm, weight 3080g, OFC 39.5 cm). We could walk independently at 2 years, say his first words at 2.5 years and could write and read at age 11 years. He was orientated early in a school for special needs. He had two hyperthermic seizures. He had severe anxiety and mood disturbances. He had partial autonomy. At last examination at age 24 years, he measured 192.5 cm, weight 60.2 kg and his OFC 63 cm (>+3 SD). He had long and thin habitus, pectus excavatum, arachnodactyly, dolichostenomelia, scoliosis, flat feet, long feet, highly arched palate, large forehead, hypertelorism, malar hypoplasia, narrow and down-slanting palpebral fissures, an open mouth, pointed chin and large neck. He had normal heart ultrasound and had strabismus, nystagmus and bilateral pallor of the papillae. Cerebral CT scan showed diffuse but moderate cortical atrophy. He had normal plasmatic homocystein level.

NFIX (MIM 164005) Trio 9

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The proband had 3 healthy sisters. There was a family history of congenital glaucoma on the father’s side. Her birth measurements were 51 cm for length, 3610 g for weight and 37.5 cm for OFC. She had severe developmental delay. She walked alone at age 2.5 years and was rapidly orientated in a school for special needs. She did not have abnormal behavior. She could associate words but did not perform sentences. He had hyperthermic seizures that were transitory treated by Depakine®. She had surgery for strabismus, and developed glaucoma. At last examination at age 18 years, her height was 171 cm (+1.5 SD), her weight 58.2 kg (75th centile) and OFC 59.5 cm (>+3 SD). She had very thin habitus, a very severe scoliosis that necessitated surgery at age 14, pectus excavatum, hyperlaxity with limited extension of the elbows, arachnodactyly with wrist and thumb signs, long feet, feet malposition and highly arched palate. She also had amyotrophy, mild mitral valve prolapse with mitral insufficiency and normal eye examination (systemic score of 9). The diagnosis of Marfan syndrome was raised and the molecular analyses of the FBN1, TGFBR1 and TGFBR2 genes were normal. Reverse phenotyping concluded that the clinical features in this patient were compatible with the implication of NFIX, gene that have been assigned to Marshall-Smith syndrome and Sotos syndrome 2 [22, 23]. Indeed, the proband had severe underweight for height, severe scoliosis, macrocephaly, triangular face with large forehead, down slanting palpebral fissures and pointed chin, which could be compatible with a Sotos-like phenotype. Sotos-like syndromes due to missense NFIX mutations usually display more severe ID and skeletal manifestations than NSD1 Sotos syndrome.

Trio 26 The proband was the first child of parents of Asian origin. There was no family history, but parents also had a long and thin habitus. His birth measurements were not known. He had mild developmental delay and epilepsy. He walked alone and said his first words at age 1.5 years. He had abnormal behavior with hyperactivity and coordination disorder. At last examination at age 3 years, her height was 102 cm (+2.5 SD), her weight 14 kg (+2 SD) and OFC 52 cm (+2 SD). He had thin habitus with a long face, hyperlaxity, arachnodactyly with wrist and thumb signs, flat feet, pointed chin, abnormal head shape with cranyostenosis, and blue sclera. He was hypotonic and had and recurvatum. X-rays showed narrow ilium and thin . Cardiac ultrasound revealed redundant mitral leaflet (systemic score of 5). Reverse phenotyping found only mild features of Marshall-Smith syndrome and Sotos syndrome 2 [22, 23].

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Solo 3 The proband had a negative family history. He was born with a length of 49 cm, a weight of 3040 cm and OFC of 34 cm. He could walk without help at 21 months, was able to construct sentences at age 5 and had to be orientated in a school for special needs. His total IQ was measured at 66. He did not have dysmorphic features except unstuck ears. At last examination at age 8 years, his measurements were normal (length 123 cm, weight 22 kg and OFC 52 cm. He had long and thin habitus, pectus excavatum, dolichostenomelia, arachnodactyly with long feet, highly arched palate (systemic score of 5). He had hypermetropia and strabismus but normal cardiac ultrasound and brain MRI. Reverse phenotyping failed in finding specific signs of the Sotos-like spectrum. The patient did not have macrocephaly or typical facial gestalt, as reported in patient B of Malan and al., 2010 [22].

NSD1 Trio 6 The proband had a healthy brother and the parents had 2 miscarriages. The father measured 170 cm and the mother 150 cm. She was born at 35 weeks of gestation (WG), with a length of 50 cm, a weight of 2700 g and occipto-frontal circumference (OFC) of 34.5 cm. Seizures were diagnosed at age 1 year, she walked at age 2 years, and she progressively developed psychotic features with severe anxiety that necessitated treatment. She developed an epidermoid carcinoma of the tongue at age 14 years. At last examination at age 16 years, her height was 171.5 cm (+2 standard deviations (SD)) cm, arm span was 178 cm. She had a marfanoid habitus including long and thin habitus, pectus abnormalities, severe scoliosis that necessitated surgery, arachnodactyly, long feet, limited elbow extension, camptodactyly, highly arched palate with dental crowding, striae and myopia (systemic score of 9). She had normal cardiac examination. After the diagnosis of NSD1 mutation, reverse phenotyping found features in accordance with the diagnosis of Sotos syndrome, considering the presence of overgrowth with progressive macrocephaly during infancy (+3 SD for all measurements), advanced bone age and learning disabilities. She only had a few craniofacial features, she did not have prominent chin, although the face was quite triangular. It has been argued that the characteristic facial appearance changes with time. As the face lengthens, the of the forehead diminishes and the chin achieves greater prominence. The mandible is long and narrow inferiorly, square or pointed, but prognathism is rare. In a small proportion of patients, a rounder face early in life may challenge diagnosis [24, 25]. A misdiagnosis of Marfan syndrome has been described in few

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instances, in adults with the aggregation of scoliosis, pectus abnormalities and arachnodactyly [24].

Trio 33 The proband had a healthy older sister and the parents are non-consanguineous with no family history. She was born at 39 WG by cesarean section for dystocia, with a length of 49 cm, a weight of 3500 g and OFC of 36 cm. Macrocephaly with was rapidly noticed in the neonatal period, associated with developmental delay and autistic features. Speech therapy and psychomotor rehabilitation were prescribed and he went to a school for special needs. He has severe anxiety disorder. At last examination at age 15 years, marfanoid habitus was found with a size of 176 cm and dolichostenomelia, pectus carinatum, arachnodactyly with positive thumb sign (systemic score of 6). He had spastic paraparesis, cerebellar syndrome, cafe au lait spots, scaphocephaly, moderate hypertelorism, eversion of the upper lip, large ears. MRI revealed mild hydrocephalus that did not necessitate treatment. He had a normal audiogram and ophthalmological examination. A deformation of the lumbo-sacral joint was found at X-rays. Cardiac ultrasound could not be performed because of the anxiety of the patient. Karyotype and Fragile X studies were normal. After the diagnosis of a CNV comprising NSD1, reverse phenotyping found features in accordance with the diagnosis of Sotos syndrome.

Solo 5 The proband is born from a twin pregnancy. He had a similarly affected older sister, and his twin brother as well as another sister did not present ID. Their parents both had ID, with similar appearance in the mother. His measurements at birth were 51 cm for length and 3090 g for weight. He had transient hypoglycaemia at birth. He had mild ID, did not have any behavioral abnormalities. At age 18, his height was 181 cm (+1 SD), his arm span 196.3 cm, his weight 51 kg and his OFC 60.5 cm (+3 SD). He had long and thin habitus, arachnodactyly with positive wrist and thumb, dolichosteomelia, asymmetric pectus carinatum, flat feet valgus, scoliosis and dural ectasia (systemic score of 11). Because of his skeletal manifestations, the diagnosis of Marfan syndrome was raised, he was treated by beta blockers and had regular ophthalmological and cardiac follow-up. He had hypermetropia, astigmatism and normal aorta. His affected sister had the following measurements at birth: 54 cm for length, 3400 for weight and 36.5 cm for OFC. She developed seizures at age 3.5 years that remained treated in

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adulthood. She also had some skeletal abnormalities of the Marfan spectrum, although milder than his brother, including hyperlaxity, scoliosis, long hand and feet, flat feet, highly arched palate with crowded teeth (systemic score of 3). She had mild ID and developed depression, phobia and anxiety that necessitated treatment. Her adult size was normal (163 cm). She had normal eye and heart survey. After the discovery of a NSD1 truncating mutation, reverse phenotyping agreed with the diagnosis of Sotos syndrome, and was inherited from the affected mother. All three had overgrowth during infancy (+3 SD for all measurements), macrocephaly, learning disabilities, and some craniofacial features. He also had a de novo NUP205 variant of unknown significance.

SCN2A Solo 8 This 22-year old female had 2 healthy sisters. She could walk at age 27 months and say her first words at age 3 years. She could write some words but not sentences, she could read simple sentences. She was orientated in a school for special needs and now works in a protective area. She had absence seizures. Clinical examination revealed a size of 170 cm, a weight of 53 kg. She had a long and thin habitus, dolichostenomelia, arachnodactyly, long, thin and flat feet that necessitate surgery, hyperlaxity, cervical and highly arched palate. She had very mild dysmorphic features, with long face, prognathism, pointed chin and malar hypoplasia. She had mild striae She had hypotonia and mild ataxia. She had mitral valve prolapse and ophthalmological examination was normal (systemic score of 9). SCN2A mutations had been described in association with a large spectrum of neurological phenoptypes, including autism [26, 27], different types or epilepsy ranging from benign familial neonatal-infantile epilepsy, generalised epilepsy with febrile seizures plus, and infantile-onset severe intractable epilepsy [28], or even more complex phenotypes such as intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities [29]. The presence of severe ID and epilepsy was compatible with this spectrum, although the marfanoid habitus was not particularly described in previous patients with SCN2A in the literature.

SLC16A2 Solo 4

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The proband had a healthy half-sister on her mother side. He was born at term, with a length of 52 cm and a weight of 3260 g. He had feeding difficulties in the first months of life. He could walk independently at age 2 years. He could associate 2 words at age 3 years. He could later write and read simple words. He had some autonomy for eating, toileting and could help at home. However, he does not have autonomy for outside transportation. At last examination at age 22 years, his height was 194 cm, weight 64 kg, OFC 58.5 cm and arm span 208 cm. He had long and thin habitus, moderate scoliosis, pectus excavatum, hyperlaxity, dolichostenomelia, arachnodatyly with long feet and highly arched palate (systemic score of 6). He had generalized hypotonia without pyramidal signs, mild superior limbs dysmetria and tremor, dysarthria, buccolingual dyspraxia, abnormal deglutition. He had normal heart survey. A pediatric Steinert disease was excluded, and electromyography was normal. After the identification of a de novo missense SLC16A2 mutation, reverse phenotyping revealed features in favor of the diagnosis of Allan-Herndon-Dudley Syndrome. Indeed, the proband had an elongated face with hypomimia, prominence of the lower lip, square jaw, open mouth and short philtrum. His hormone levels were abnormal, with elevated T3 and normal TSH. Some data can explain some overlap with marfanoid habitus and ID spectrum, since some patients display asthenic build/muscle hypoplasia (88%), narrow, long face (75%), scoliosis (53%), pectus excavatum (58%) and contractures (59%) [30]. However, he presented with a milder neurological phenotype compared to the usual descriptions in the literature. Some genotype-phenotype correlations have been discussed in order to explain clinical variability [31].

SLC6A1 Trio 4 This patient had 3 healthy sisters and 2 healthy brothers. The parents also had a miscarriage. His measurements at birth at term were 53.5 cm for length, 4220 g for weight, and 37 cm for OFC. He could walk at age 15 months, he could express his first sentences at age 3 years, and could write and read since the age of 8 years. He had severe speech difficulties. He displayed mild ID with severe psychiatric manifestations, including major anxiety, major inhibition with social deficit, attention deficit disorder, autoisolation, rites, in particular by putting hands in his mouth, selection of food, urinary incontinence. He was not orientated in a school for special needs, but was two years behind with a management by speech therapy, occupational therapy and psychiatry. He needed the presence the presence of an adult for outside travels.

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At clinical examination at the age of 16 years, his size was 181 cm, his weight 54 kg and OFC 59 cm. He had a long face, down slanting palpebral fissures, prominent nasal bridge, posteriorly rotated protruding ears, microretrognathism and teeth malposition. He had long and thin habitus, pectus excavatum, arachnodacytly, dolichostenomelia, severe scoliosis that might necessitate surgery, limited extension of elbows, hyperlaxity, flat feet and highly arched palate (systemic score of 9). He had nasal speech. He had normal genitalia and normal puberty. Neurologic examination showed difficulties in walking on his with balance and fine motor difficulties. He also had myopia, but had a normal aorta. His cerebral MRI was normal. The SLC6A1 gene has been published in association with developmental delay and epilepsy [32]. This gene was the candidate gene for the 3p25.3 microdeletions, reported in individuals with a wide spectrum of neurodevelopmental disorders.

TAF1 Trio 10 The patient had 3 unaffected brothers and sister. He was born at term with intrauterine growth retardation (length 45 cm, weight 2500 g, OFC 33.5 cm). He had congenital torticollis. He walked independently at 24 months and later developed regression of walk. He could say a few words but did not develop sentences. He had epilepsy and psychotic behavior. He was orientated in a school for special needs for moderate ID. He had major scoliosis (80°) that required thoracic and lumbar arthrodesis. He had Klippel-Feil-like cervical malformations. He had long and thin habitus but could not be measured, arachnodactyly with positive thumb and wrist signs, long feet (systemic score of 5). He had facial dystonia, long face with pointed chin, prominent supraorbital ridges, malar hypoplasia, simple ears. His cerebral MRI revealed corpus callosum agenesis, posterior periventricular heterotopia of the grey matter. He had unilateral strabismus and normal heart survey. He progressively developed tracheal spasm that necessitated tracheotomy. He had walking difficulties. The TAF1 gene has been assigned to dystonia- without ID in 2017 in association with retrotransposon insertions [33], and later to X-linked syndromic ID in association with missense TAF1 variants. This patient has participated to the description of this new phenotype [34].

TBR1 Solo 25

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The proband was born at 38 WG with an Apgar score of 9/10. There was no family history. Birth measurements were 3180 g (15th centile) for weight, 51 cm (-1 SD) for length, and 34 cm (-1 SD) for OFC. He presented mild developmental delay, acquired the sitting position at 9 months and walked at 17 months. Language was severely delayed with his first words pronounced at 24 months. ID was associated to behavior disorders including autistic features as rare ocular contact, inhibition, high level memory, echolalia, stereotypies, rituals, but also attention deficit hyperactivity disorder and sleeping disorder. Wechsler Preschool and Primary Scale of Intelligence (WPPSI): 44 at 5 years, Wechsler Intelligence Scale for Children (WISC IV): 48 at 11 years. Facial dysmorphic features included long face, plagiocephaly, high forehead, enophtalmy, deep set eyes, highly arched palate, and thin upper lip. He presented a marfanoid habitus with mild dorsal kyphosis, arachnodactyly with positive thumb and wrist sign, dolichostenomelia, and mild global joint laxity (systemic score of 5). Neurological exam only revealed rare tremor, and cerebral MRI realized at 12 years showed large Virchow Robin spaces in superior parietal regions. Cardiac ultrasound was normal at 14 years. He also presented acrocyanosis and moderate constipation. At last examination at 24-year-old, weight was 70 kg (+1 SD), size 195 cm (+3 SD), and OFC 57 cm (mean). Arm span was at 202 cm (ratio 1.03). Clinical presentation is compatible with the sparse clinical descriptions [35].

ZBTB18 The proband was the second child of unrelated healthy parents. Pregnancy and neonatal periods were uneventful, with a birth weight of 3170g, a length of 51 cm and OFC of 32 cm at term. He sat at 10 months, walked at 22 months. He was treated for epilepsy since the age of 14 years and had anxiety disorder. Language was severely delayed with the first words at 16 years. He went in a school for special needs. At last examination at 20 years, we could not read or write. He attended an occupational institution. He had a long and thin habitus, with a height of 188 cm, scoliosis, long and thin hands and feet, feet malposition, highly arched palate (systemic score of 4). He had a long face, malar hypoplasia, pointed chin and teeth malposition. He had abnormal visibility of his vessels. He had normal eye and aortic examination. Brain MRI showed posterior agenesis of corpus callosum. Trio 24 has been published in Depienne et al., 2017 [36].

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ZBTB20 Trio 1 The proband was the third child of unaffected parents. She was born at term, and measurements were 52 cm for length, 3500 g for weight and 37 cm for OFC. She had hypotonia in infancy and sat at 16 months, walked independently at 26 months and had speech delay. She had peculiar facial features such as down slanting and narrow palpebral fissures, small mouth, small chin and large ears. She had severe constipation and progressively developed amyotrophy of the scapular area and generalized muscular deficit. She had long and thin habitus, scoliosis, hyperlaxity, contractures of elbows and knees, long hands and feet, highly arched palate. She also had cutis laxa and emaneal dysplasia. Muscle histology did not reveal a sign in favor of a myopathic process, cerebral MRI was normal and evoked auditory potentials evidenced a mild transmission hearing deficit. Heart ultrasound was normal. She had negative metabolic testing including O and N glycosylation and mitochondrial testing, sequencing of TGFBR1 and 2. She was orientated in a school for special needs. She had surgery for scoliosis at age 18. At last examination at age 20, her length was 148 cm, her weight 37 kg and OFC 54 cm. After the discovery of a missense ZBTB20 de novo mutation, reverse phenotyping permit to raise the diagnosis of Primrose syndrome [37]. Indeed, the proband had some common dysmorphic features including wide forehead, ptosis with downslanting narrow palpebral fissures, ptosis, hypoplastic alae nase, small mouth and small chin, associated to progressive muscle wasting. Retrospective search for ectopic calcifications and was negative. This observation showed the difficulty in raising a diagnosis in very rare entities, which are unknown to most of the clinicians until the identification of their molecular bases.

ZEB2 Trio 14 The proband had two healthy brothers. His measurements at term were 50 cm for length, 4250 g for weight and 36 cm for OFC. He had surgery for severe gastro oesophageal reflux, common mesentery and cryptorchism. Generalized epilepsy was diagnosed at age 1 year treated with bitherapy. He could seat at age 18 months, walked independently at age 2.5 years and said his first words at age 5 years. He could make sentences at 20 years only, and could not read or write. He was orientated early in a school for special needs. He had psychotic behavior with abnormal sexual behaviour that necessitated treatment. When he was last seen at age 20 years, his size was 172 cm with an arm span of 180 cm, a weight of 60 kg and an OFC of 58.5 cm. He had long and thin habitus, dolichostenomelia,

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arachnodactyly, long feet (shoe size 44), flat feet, highly arched palate (systemic score of 5). He had myopia and strabismus. External genitalia examination showed large testes and penis. Cerebral MRI was interpreted as normal. After the identification of a de novo frameshift ZEB2 mutation, reverse phenotyping revealed some facial features in favor of the diagnosis of Mowat-Wilson syndrome (MWS), including broad and horizontal eyebrows, telecanthus, central depression of the ear lobes, long and convex nasal tip overhanging the philtrum with prominent columella. However, some other classical facial features are missing, such as the microcephaly, frontal bossing, medially flaring and sparse in the middle part of the eyebrows, deep-set eyes, epicanthic folds, uplifted ear lobes, full cheeks and pointed chin. Besides facial features, all the common features found in MWS were absent (constipation or Hirschprung disease, , urogenital/renal anomalies, hypospadias, short stature, hypoplasia or agenesis of corpus callosum). This observation is a good example of the difficulty of recognizing the adult phenotype of patients with known Mendelian diseases. The evolving facial phenotype with age has been described in the literature and need to be known since the distinctive facial appearance is considered as one of the most specific clinical signs in MWS [38]. Indeed, eyebrows, that are sparse during childhood, tend to become heavier, broad and horizontal, usually with an increasingly wide longitudinal separation, in adolescent and adults. The shape of the face also changes greatly from infancy to adulthood. It appears round, with frontal bossing and full cheeks at an early age. Later on, the face tends to become more elongated and the jaws more prominent, with full lips, prominent mouth, and long and pointed chin. The nose presents with depressed nasal bridge and rounded nasal tip in children, but the nasal tip lengthens with age overhanging the philtrum, the columella becomes distinctly prominent, giving rise to the appearance of a short philtrum and a more convex nasal profile. The uplifted ear lobes do not change significantly over time with the exception of the central depression, which is less remarkable in adults.

Trio 28 The boy was born at term after an uneventful pregnancy. Weight was 3770 g and length 51 cm. Family history was unremarkable. He was the second child of unrelated young parents. He walked at 14 months. Language skills were delayed. At age 7 years, he underwent special schooling. Weight was 23 kg (mean), length was 128.5 cm (+ 1 SD) and OFC 52 cm (mean). Habitus was marfanoid with dolichostenomelia, arachnodactyly, scoliosis, and highly arched palate (systemic score of 6). Facial features included high forehead, low frontal implantation of hairs, cowlick, marked nasal root, down-slanted palpebral fissures, and dysplastic ears with

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anteverted lobes. He had a shy and anxious behavior. He had no constipation. At age 9 years, global IQ was evaluated at 50 (WISC-III). He could read and write at age 11. At age 17 years, weight was 57 kg (- 0.5 SD), length was 178 cm (+ 0.5 SD), and OFC was 56 cm (+ 1 SD). Three supernumerary teeth were noted. Cardiac ultrasound examination showed a mild aortic insufficiency. Renal ultrasound examination was normal. Ophthalmological examinations showed a bilateral keratoconus. Brain MRI and EEG were normal. Chromosome analysis and CGH-array analysis were normal. Fragile X testing was negative. Exome sequencing revealed a de novo ZEB2 (c.2995G>A, p.Gly999Arg), but also a de novo variant of unknown significance in SYNGAP1 c.2047A>G with non- convincing scores of pathogenicity (Polyphen 0.313, GERP 4.940, Grantham 29).

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