Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. 05.O these, Of 2015). coemldslsa(E) codn oTzca(reik&Kcoosi 06,teehv en345 to been due have are there 206 2016), which of Koczorowski, hypohidrotic HED, & of Trzeciak(Trzeciak of cases to of cases 95% According reported for (HED). accounts which dysplasia (XLHED), ectodermal dysplasia ectodermal hypohidrotic X-linked with embryonicBl 58 in about role 2019) EDAR important al., an 2001). plays et Mikkola, Yu and & by Thesleff, 2016) caused Laurikkala, dysplasia al., Pispa, Ectodermal et Koppinen, pathways(Shen 2011; and al., BMP superfamily, et receptor and development(Cluzeau TNF WNT ectodermal the the to of (NF- shown to member B been a crosstalks kappa has (EDAR), factor (EDA1) nuclear receptor the Ectodysplasin-A1 ectodysplasin-A activate (STA). the agenesis to tooth specifically syndromic bind and (NSTA) agenesis tooth most the of of variants 2016), one with al., is associated failure(De et agenesis developmental be to a tooth known to (selective) is due EDAR Non-syndromic and teeth 2009). anomalies of dental Huysseune, absence common & the involving Martens, condition Marks, pathological Coster, a is agenesis Tooth families. NSTA in prediction 1 status correlation Genotype-phenotype c.338G disease improve mutation, gene. to EDAR by missense help the characterized EDAR could of were novel mutation spectrum patients EDA1 mutation A reported and the NSTA EDAR extending molars. in premolars NSTA, of EDA1 first with first analyses of pedigree maxillary maxillary a 289 the the in codon and identified affecting at incisors, was rarely mutations lateral c.865C of loss, maxillary patients: phenotype the incisors three The lose lateral in to affected. identified likely least c.338G were most the mutation mutations were were EDA1 novel Whole patients NSTA three A mutations. that addition, new showed In 4. investigate mutation Family to pedigree. DNA sequenced for a for c.866G and in collected performed (Arg289Cys), identified PCR were then NSTA a was by were with gene amplified provide pedigrees EDAR sequencing was to four the gene Sanger and of EDA1 and (NSTA) samples the sequencing agenesis blood of Peripheral exome tooth region pathogenesis. coding non-syndromic its The for of responsible extraction. study the genes for pathogenic basis of genetic mutations novel investigate To Abstract 2020 11, September 1 Liu Zhang Hongyu Chinese a in Family Agenesis Exome Tooth Whole Non-Syndromic by with Identified Sequencing Mutation Missense EDAR Novel A ee eia University Medical Hebei | ka ua ai,22;Zn ta. 07.Similarly, 2017). al., et Zeng 2020; Malik, & Huma, ukba, ¨ INTRODUCTION 1 igin Meng Lingqiang , , aebe on nptet ihNT(ree l,21;Jnsne l,21;Mma,Nalbant, Mumtaz, 2018; al., et Jonsson 2013; al., et NSTA(Arte with patients in found been have EDARADD LRP6 1 EDA > unigKong Xuanting , Okle ta. 06 .Y,Wn,Hn a,21)and 2019) Cai, & Han, Wong, Yu, M. 2016; al., et (Ockeloen Ag8Hs,adc.1013C and (Arg289His), A , WNT10A , EDAR 1 uzogZhang Guozhong , EDAR , At,Prae,Prnn lluu,&Neie,2013), Nieminen, & Alaluusua, Pirinen, Parmanen, (Arte, EDAR EDARADD uain aebe on nSA oee,ol ee uain of mutations seven only However, STA. in found been have mutations 1 iboRen Jiabao , uain aebe ieyrpre;acrigt .Y tal.(M. et Yu M. to according reported; widely been have mutations κ )(a ta. 00.TeEDA-EDAR-NF- The 2000). al., et (Yan B) > Tr3Mt.Gntp-hntp orlto nlsso DRgene EDAR of analysis correlation Genotype-phenotype (Thr338Met). T and , 1 EDA1 igigDu Qingqing , WNT10A 1 1 hoYuan Shuo , uain.A t21,teHmnGn Mutation Gene Human the 2017, at As mutations. EDA1 r addt ee fbt non-syndromic both of genes candidate are 1 n ejn Shen Wenjing and , steol eekont eassociated be to known gene only the is 1 hna Liu Chunyan , MSX1 GREM2 , PAX9 κ inln pathway signaling B 1 Knaur tal., et (Kantaputra a Hou Yan , , AXIN2 > 1 WNT10B Cs1Tr in (Cys113Tyr) A > (Cys113Tyr), A , EDA1 1 P Yu (P. Ye , > T , Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. n h C rdcswr eune sdsrbdi eto ..Terfrnesqec for sequence reference The 2.3. Section Build in described Human as The Consortium a sequenced ANNOVAR. Reference achieved were by were NM annotated products samples Genome indels then PCR the small the and the the and (GATK) bases, to and Toolkit variants from raw aligned Analysis of Single-nucleotide exons Mb were mutation Genome candidate the 17,550 and Reads Aligner. SAMtools than sequence Burrows-Wheeler with 6000 more to the x. identified NovaSeq of with used 138 Illumina (GRCh37/hg19) yield was of 37 sequencing USA) depth Ltd. a capture CA, target Co., any With liquid-phase Diego, China) mean have via San (Beijing, not regions. performed (Illumina, Bioscience did targeted were iGeneTech platform who amplification from Analyzer 4), and kits (Family Genome enrichment testing proband Target with the PCR. method for by performed detected was tations sequencing exome Whole 72degC Beijing, 2.4 Biotech- s, for Institute, the Center 30 Genomics National of the Beijing for of 4 the database 60degC EDA1 by BLAST exon ( the s, sequenced of using Information was analyzed 30 of Primers was nology DNA sequence for volume 95 and nucleotide 95degC The total min. electrophoresis at China. gel at a 7 denaturing agarose cycles in for by After 35 elicited 72degC tested USA). were was finally follows: Amplification Fisher, 5’-GTTAATGGCCACTTAGGAGACAC-3’. reactions and R: as GGCAAGAGTAGCTTCTGGAGAC-3’; (Thermo PCR s, out Polymerase 30 carried 2009). DNA for was Taq al., amplification TransStart et min, U Song 1.25 the 2018; of and al., exons et coding al(Feng eight 50 et the Song amplify to by used primers The lo ape eecletduigET satcauat N a xrce rmluoye using leukocytes from stored and extracted GA) was Omega, 2.3 Kit, DNA Midi anticoagulant. DNA Blood as -20 (E.Z.N.A. EDTA Peripheralat methods University. chloroform using Medical phenol Hebei collected Stomatology, proteinase-K of standard were Hospital and samples School the blood at patients were probands The N:[06 0) l atcpnso hi urin indwitnifre consent. University informed Medical written Hebei Stomatology, signed under of guardians conducted Hospital their was 2.2 and or study School participants The ra- the All 1). panoramic of 004). (Figure the Depart- and Committee [2016] teeth non- performed, determine Ethics of (NO: the were 100 absence the to history congenital of and to treatment approval the specialists University, dental the confirm referred a prosthodontics Medical to and taken by were Hebei examination were oral examined of diographs who An Stomatology were dentition. NSTA of of participants status with Hospital All and patients controls. School consanguineous non-consanguineous Prosthodontics, four of involved ment study The mg (https://www.ebi.ac.uk/Tools/msa/clustalo). Omega mutations. NSTA, by for 2.1 caused mutations NSTA gene for pathogenic correlation potentially genotype-phenotype the a investigate 2 and to mechanism is genetic study a our provide of to aim The analyzed. ( of were published mutation mutations all missense of missense novel phenotypes a previously-reported investigate three we as study, present the the in In mutations 314 registered had 2018). 2017.2) Professional (HGMD Database | μ ,ec otiig10gDA 4 DNA, 100ng containing each l, AEIL N METHODS AND MATERIALS | | | | 2364 rs-pce lgmn fteaioai euneo DRwspromdb Clustal by performed was EDAR of sequence acid amino the of alignment cross-species A 022336.4. hl xm eunigadSne sequencing Sanger and sequencing exome Whole C mlfiainadmtto screening mutation and amplification PCR ° extraction and collection sample DNA ujcsadehclapproval ethical and Subjects C. and EDAR ee n 0 neae ouainmthdcontrols. population-matched unrelated 100 and genes https://blast.ncbi.nlm.nih.gov/Blast.cgi EDAR EDAR a eie ihPR olwdb agrsqecn.PRwsperformed, was PCR sequencing. Sanger by followed PCR, with verified was uatptet n uain tcdn29of 289 codon at mutations and patients mutant μ NP,5l10 5ml dNTPs, l 2 EDA1 × .W dnie h uloievrat nthe in variants nucleotide the identified We ). EDA1 rnSatTqBffr 0.2 Buffer, Taq TransStart nCieeHnfmle.Tegntpsand genotypes The families. Han Chinese in EDAR eei C eebsdo hs used those on based were PCR in gene EDAR c.338G EDA1 eewr sflos :5’- F: follows: as were gene > .Cs1Tr,a well as Cys113Tyr), p. A EDA1 eeRysRaie al., et gene(Reyes-Reali μ nNT patients NSTA in fec primer, each of l EDA1 EDAR ° o 5 for C mu- was Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. nios(67)aels ffce.I spriual neetn htmxlayfis oasaepeeti all in present are molars central first maxillary maxillary and that interesting (16.7%), particularly molars is first premo- It 5). mandibular second (Figure affected. mandibular (8.3%), the patients less the molars of are and of second volume (16.7%) (91.7%), 289 the the incisors incisors codon However, central properties, at mandibular mutations physicochemical Al- (75.0%). the reported in lars residue. 91.7%), that change p.Arg289Leu (100%, non-polar shows a The incisors a analysis cause lateral to Phenotype 2009)). not al., residue decreased. et positively-charged did chain Song a mutation side 2016; from Arg289His al., change the et a Ruiz-Heiland though caused 2014; mutations al., p.Arg289Cys 4). et (Figure and (Lee teeth 3, (Table anterior studies of previous that than lower mandibular is Two the molars by the followed the of (6.7%), include loss lowest not of is 3.4 rate does premolars the first this the maxillary all, although (43.3%), the In incisor (33.3%); of (10%). lateral premolars rate with canines mandibular missing second patients the The NSTA the by In molars. and followed third (83.3%), (40.0%), 2. rate incisor Table missing central in highest mandibular listed the are had incisor teeth lateral missing the of details the of sites mutation from data summarized and seven studies published four reviewed We the that showed EDAR of alignment sequence ( acid humans brother and amino among father cross-species conserved his A while highly 2B), was (Figure location. site sequencing this Sanger mutation at by mother type and his wild was and (0.996), mutation were 4 Candidate damaging” proband pathogenic. “probably for highly confirmed was (0.00), variant then “deleterious” the suggesting were respectively, mutation (1.00), “disease-causing” ”MAF the new by a for technology found the predictions We sequencing of MutationTaster 4. sequences exome Family coding in whole the found using screening was After by mutation no gene. causative PCR, the by determine gene to aimed we diagnosis, After 3.3 1). (Figure normal. be to observed were the nails on and hair dry skin, had of participants features, complaints The 3.2 facial no conical parents infections. their or had tract and their small They respiratory have scalp, of to secretions. not and None susceptibility lachrymal did body or normal. mothers and heat, were extensively and sweating to teeth, teeth normal distributed intolerance The missing residual mouth, reported be congenitally the participants 1). to had of All 4) Figure found sizes proband teeth. molars, and and of third radiographs shapes mother the panoramic the the However, (except by (excluding oligodontia, confirmed teeth dentitions. congenital was both permanent exhibited in teeth 8-18 all permanent and families NSTA of teeth four loss deciduous the 6-10 from probands missing four each of examination clinical The 8 rmecdn r oHs o ain ,teewsapTr3Mt(c.1013C p.Thr338Met a was there 3, patient For His. in to Arg of reported encoding been from (c.866G p.Arg289His 289 previously A Cys. have to Arg (c.865C patients p.Arg289Cys the oligodontia 1, tient in found c.1013C c.865C mutations the ons: of Three ( chickens and ( 3.1 3 > EDA1 | NP RESULTS | | | | hntpso SAptet with patients NSTA of Phenotypes EDA1 hntpso SAptet with patients NSTA of Phenotypes uainaayi of analysis Mutation lnclfeatures Clinical EDAR 0183.) hssmnes( monkeys rhesus 001108536.2), > hnigcdn38fo noigTrt Met. to Thr encoding from 338 codon changing , Tr3Mt(a ta. 08 Fgr ) l fwihaelctdi h N oan npa- In domain. TNF the in located are which of all 3), (Figure 2008) al., et (Thr338Met)(Han T > uain (c.865C mutations uain(ree l,21;Jnsne l,21;Mma ta. 00 ege l,21) The 2017). al., et Zeng 2020; al., et Mumtaz 2018; al., et Jonsson 2013; al., et mutations(Arte Ag8Cs(oge l,20) c.866G 2009); al., et (Arg289Cys)(Song T > NP 0022.)(iue2C). (Figure 001012629.1) EDAR ee rti hne,adtetpso uain r ie nTbe1 The 1. Table in given are mutations of types the and changes, protein gene, EDAR > > n c.866G and T )mtto cusi xn7of 7 exon in occurs mutation T) > )mtto a on neo of 7 exon in found was mutation A) > and XP EDA1 1988.) os( dogs 014968589.2), EDAR > EDA1 )a oo 8 eerpre norsuya ela in as well as study our in reported were 289 codon at A) 3 > uain tcdn289 codon at mutations mutations NP < % n eoi”fitrn.SF,Plpe2and Polyphen2 SIFT, filtering. ”exonic” and 1%” > 7711,ctl ( cattle 071731.1), (r29i)Ri-eln ta. 06;and 2016); al., et A(Arg289His)(Ruiz-Heiland EDAR > EDA1 XP EDAR rltdNT ainswt oa of total a with patients NSTA -related 0662.) ie( mice 005626028.2), hnigcdn29fo encoding from 289 codon changing , EDA1 uainc.338G mutation EDAR > fptet2 hnigcodon changing 2, patient of XP uain,temaxillary the mutations, > 0228.) zebrafish 005212787.1), )mtto neo 8 exon in mutation T) EDA1 > > (Cys113Tyr) A NP EDA1 ffcsthe affects 034230.1), EDA1 ex- Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. h idtp DEA tutr,teAg8 eiu slctda h ue ufc ftehmtie and electrostatic homotrimer and in the bonds that of hydrogen found surface forms and outer Arg289 protein the addition, al., EDA1 at In the et located Asn272. on is interface(Hymowitz with analysis residue bonds monomer–monomer structural Arg289 hydrogen out the the structural structure, carried makes at EDA1 2009) receptor 3D (c.865C al., wild-type mutations et the the al.(Song the with et of interaction of Song Two domain for 2000). TNF 3. required the and in is 2, located which 1, were Family study in this in characteristics line these maternal the that the in from confirmed found also were 2016) mutations the shared al., three research, et 24 and al.(He our followed incisors studied by central incisors et In 2008) caused maxillary lateral He NSTA al., the the of of were et were phenotypes teeth results teeth al.(Han missing specific The missing likely were et likely least molars. Han the most permanent and the Liu, 2011). first incisors; that He, central al., found mandibular 2008; et They the al., Zhang by dentition. et 2018; of deficiency(Han al., been position tooth each had et mutations Wong congenital with different from for 2016; patients 198 derived Feng, phenotype NSTA decades are & and two 27 Liu, genotype past the which the Han, the in of over between differences NSTA, 2019), link the for al., factors. clear that responsible et epigenetic permanent Yu hypothesized are or 17 al.(M. We that polymorphisms and et detected nucleotide Yu skin. 18 single M. or signs had with to no hair associated mother According with the be his presented might in and participants teeth with as proband our missing patients such but the of in study, studies, hypoplasias, number previous present lost ectodermal from teeth the other differs is permanent In of This cases, of respectively. 10. TA number missing, EDAR-related to the teeth those 2 particular, in mutations from In commonly to ranged sensitive most NSTA finding. involved are our were incisors, to incisors the similar permanent especially and teeth, be anterior deciduous to most that likely both the least seems the that It were the the observed canines 4). and in also mandibular incisors Figure and We lateral 2; premolars mandibular (Table first the 1). maxillary affected by (Table followed The mutations incisors, incisors. lateral missense central maxillary mandibular were the were (6/8) teeth mutations missing of common with majority patients the NSTA nuclear and downstream all of of of activation information (5/8) the the affecting studying with ultimately By affinity EDARADD, its to alter might binds EDAR of instead 2019). (NF)- substitution al., it factor p.Cys113Tyr et the that Parveen that 2001; so speculated al., We EDA1, et EDA1. Outi to 2019; binds Shimomura, factor that & nuclear Yasuno, downstream (c.338G Asano, activates p.Cys113Tyr intra- Okita, turn its The 2011; in in al., This domain et complex. death Masui a EDARADD a 2001; intracellular form as (NF- and well to cysteine- EDA1 B as regions a extracellular intracellular 5), kappa has with and and It interacts extra- 4 EDAR superfamily. the 3, receptor 12). via exons exon TNF by by the (encoded (encoded of region region member cellular extracellular a result the and Our in al., protein domain transmembrane variant. et rich I the type Zeng of a pathogenicity is 2020; high EDAR of al., the sequences of implying acid et spectrum amino species, mutation Mumtaz of seven the alignment across 2018; expands cross-species conserved A al., was several mother. p.C113 et his years, that and Jonsson recent 4 Patient new 2013; In in a sequencing study, al., our 2019). et In al., identified(Arte 2017). et been of phenotype(Parveen have variants HED pathogenic patients registered the 62 have has 2018.3) 50 Professional, (HGMD Database Mutation the of Mutations 4 | DISCUSSION EDAR EDAR EDA1 κ B. κ ee ree l At ta. 03adMma ta.(utze l,22)fudthat found 2020) al., et (Mumtaz al. et Mumtaz 2013)and al., et (Arte al. et Arte gene. )t eit rncito ftetre eeKmr b,Sna amn Chaudhary, & Jasmin, Sinha, Eby, gene(Kumar, target the of transcription mediate to B) uain nNT ainswr ocnrtdi h et oanecddb xn12, exon by encoded domain death the in concentrated were patients NSTA in mutations EDAR uain ihtermte Fgr ) niaigta h uatallswr inherited were alleles mutant the that indicating 3), (Figure mother their with mutations EDA1 eecnrsl nHDAK ta. 07 ege l,21) h ua Gene Human The 2018). al., et Feng 2017; al., et HED(A.K. in result can gene > EDAR )mtto neo cusi einta noe h ytierc domain cysteine-rich the encodes that region a in occurs 4 exon in mutation A) uain n odce ttsia nlsso h ubro isn et in teeth missing of number the on analysis statistical conducted and mutations isnemtto .3 G c.338 mutation missense EDAR . EDA1 EDA1 mutations. EDA1 4 h N oooydmi om homotrimer, a forms domain homology TNF The . EDAR eeo lgdni ain -.Teprobands The 1-3. Patient oligodontia of gene > (y13y)wsdtce ywoeexome whole by detected was A(Cys113Tyr) uain,w on htmr hnhalf than more that found we mutations, EDA1 > rvossuisrvae a revealed studies Previous . EDAR n c.866G and T uain nNSTA in mutations EDAR EDAR EDAR > )observed A) fwhich of , -related showed Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. r osre cossvnseis h uatall smre nterdbx ,idct completely a indicate *, box. red chro- the sequencing in residues DNA marked six 3 (B) is other FIGURE the allele proband. that mutant acids. show the The amino results to of alignment species. column points Sequence conserved seven (C) arrow across black mother. conserved his the and are 4; proband Family the NSTA of of matograms pedigree The mandibular. radiog- (A) Mand: Panoramic maxillary; (C) probands; Max: of teeth; 2 teeth missing FIGURE missing indicate intraoral squares of Black Legend probands. (B) of probands; raphy of image Intraoral (A) 1 FIGURE legends interest. Figure of conflict no declare authors The interest: of Conflict (https://www.ebi.ac.uk/Tools/msa/clustalo) EMBL-EBI (https://blast.ncbi.nlm.nih.gov/Blast.cgi) Information Biotechnology Medical for Hebei Center of National Medicine and experiment. Forensic team the of in project College the the support resources to technical of Web with grateful and members help very instruments the their also lab all for are providing thank We study for to this efforts. University like in their would participated for We who teachers analysis. personnel the and medical diagnosis, and collection, subjects sample the all thank sincerely We reasonable upon author corresponding the Acknowledgements: from available are study this of findings request. the support that fetus data The and screening families. prenatal NSTA statement counseling, in availability to genetic prediction Data us preconception status allowed disease in to help This contribute could which research patients. diagnosis, This NSTA agenesis. in tooth previously-reported correlation studied genotype-phenotype we addition, the their In expand summarized pathogenic. highly and is mutations mutation this that to suggest due new analyses a loss identified teeth study of The phenotype the of to analysis changes phenotypic 5 slight studied. partic- Our the be is to causes It patients. remains that all mutations mechanism affected. protein in of the less present However, 289 were were incisors codon molars mutations. central maxillary at first contrast, maxillary all mutations maxillary In and that the the premolars. molars found that second first mandibular interesting and and mandibular ularly analysis incisors of molars, genotype-phenotype mandibular p.289 second by a at followed the performed affected, occurred We are changes incisors all different. lateral these although slightly abolish that would were noting impact location tients worth partly p.289 receptor. is domain EDA the TNF it to at the However, protein Variants in EDA mutations 2009). of 289 binding al., codon the Therefore, et et on stability. unit(Lee Song protein asymmetric 2016; reduce multi-trimer al., and the interactions et stabilize to Ruiz-Heiland homotrimer(s) 2014; adjacent al., the of Glu308 with interactions | CONCLUSION EDAR eire n uainifraini SAFmle 1-3. Families NSTA in information mutation and Pedigrees 4. Family NSTA in gene EDAR the of mutation missense a of Identification (NSTA). agenesis tooth non-syndromic with probands four the of Characteristics uainsetu swl spoiigagntcbssfrteptoeei fcongenital of pathogenesis the for basis genetic a providing as well as spectrum mutation EDAR EDA1 uainc.338G mutation scnitn ihtetpclpeoyersligfrom resulting phenotype typical the with consistent is > 5 Cs1Tr,adbt osraieadpathogenic and conservative both and (Cys113Tyr), A EDA1 h hntpso pa- of phenotypes the , EDA1 EDAR gene Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. atpta .N,Kegha . asdli . oe,P,Kwsk,K,Oaaa . Ketudat & Anomalies. A., Dental Ohazama, and K., Mutations Kawasaki, 2 Stefansson, P., GREMLIN Vogel, . A., (2015). . Hatsadaloi, R. M., J. . Agenesis. Kaewgahya, Cairns, B., Tooth N., Feenstra, of P. F., Risk Kantaputra, Geller, Conferring Variants T., Common Jonsson, A and A., doi:10.1177/0022034517750109 (2000). Rare Thordarson, R. E., Kelley, (2018). T. K. . Magnusson, . Apo2L/TRAIL. L., Homotrimeric . Jonsson, of phenotype A., Structure Ashkenazi, and X-ray K., High-Resolution screening Totpal, a mutation 39 A., by Biochemistry, EDA Revealed Hurst, Site M., (2016). Zinc-Binding Ultsch, L. Unique M., H. O’Connell, Feng, S., mutation & Hymowitz, EDA C., Novel H. agenesis. (2008). Liu, tooth S. D., with doi:10.3969/j.issn.1671-167X.2016.04.024 Song, Han, patients . Y., in Liu, analysis . agenesis. Y., tooth . H. isolated X., He, EDA-associated Wang, 51 of M., pattern Genet, Yan, Med the and X., J hypodontia Eur Zhang, Mutations non-syndromic H., Gene X-linked Wu, EDA in Two Y., resulting Gong, (2018). D., M. Han, Qi, & P., Yu, Dysplasia. doi:10.1111/jdv.14874 F., Ectodermal Huang, e326. Hypohidrotic with JunhuiSun, Patients T., Chinese Wei, in C., Weng, clinical X., and Feng, genetic agenesis: Dental (2009). [pii] A. JOP699 Huysseune, & (2011). C., L. A. Martens, hypohidrotic/anhidrotic Smahi, A., of L. perspectives. . Marks, 90% J., . P. for Coster, account . De S., WNT10A) Masmoudi, and P., EDARADD, cases. Guigue, signaling EDAR, dysplasia S., EDA (EDA1, ectodermal Mansour, and genes M., WNT four Jambou, for Only S., tooth role Hadj-Rabia, of significant C., analysis suggests gene Cluzeau, and Candidate genes p.L397H (2013). P. six combinations. EDAR Nieminen, allele in novel & and mutations S., The novel Alaluusua, identifies S., (2017). Pirinen, agenesis S., Dalal. Parmanen, S., . Arte, dysplasia. 31 Venereology, . ectodermal & hypohidrotic Dermatology . dominant of Academy autosomal Nagarajaram, causes H.A., mutation Mohapatra, missense R., Chaudhary, missing A.K., tooth indicate Mo, stripes premolar; Dark PM, dentition. REFERENCES canine; maxillary Ca, of incisor; dentition. rate mandibular missing lateral of tooth LI, rate indicate incisor; stripes central Light CI, molar. mandibular; Mand, maxillary; Max, missing tooth indicate molars). Mo, stripes premolar; Dark 5 PM, dentition. FIGURE canine; maxillary Ca, of incisor; dentition. rate mandibular missing lateral of tooth LI, rate indicate incisor; stripes central Light CI, molar. mandibular; Mand, maxillary; chro- Max, sequencing DNA in 4 bases FIGURE unaffected. mutated c.865C all are the mutations fathers indicate heterozygotes, EDA1 arrows all Red reported Three c.1013C probands. the to matograms. point arrows Black > Tr3Mt eeietfidi h rbnso SAfmle -.Mteso ainsare patients of Mothers 1-3. families NSTA of probands the in identified were (Thr338Met) T ot isn aeo SAptet ihEA uain tcdn29(xldn h third the (excluding 289 codon at mutations EDA1 with patients NSTA of rate missing Tooth ot isn aeo SAptet ihEA uain ecuigtetidmolars). third the (excluding mutations EDAR with patients NSTA of rate missing Tooth rlPto e,38 Med, Pathol Oral J 3-4.doi:10.1021/bi992242l 633-640. , 6,5656 doi:10.1016/j.ejmg.2008.06.002 536-546. (6), LSOe 8 One, PLoS u ua,32 Mutat, Hum 1,11.doi:10.1111/j.1600-0714.2008.00699.x 1-17. (1), 8,e30.doi:10.1371/journal.pone.0073705 e73705. (8), ora fPkn nvriyHat cecs 48 Sciences, Health University Peking of Journal 1,7-2 doi:10.1002/humu.21384 70-72. (1), 1,e7e0 doi:10.1111/jdv.13587 e17-e20. (1), 6 > Ag8Cs,c.866G (Arg289Cys), T u cdDrao eeel 32 Venereol, Dermatol Acad Eur J etRs 94 Res, Dent J etRs 97 Res, Dent J ora fteEuropean the of Journal > Ag8Hs,and (Arg289His), A 1) 1646-1652. (12), 4,686-691. (4), 5,515-522. (5), 8,e324- (8), Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. reik .H,&Kcoosi .(06.Mlclrbsso yoirtcetdra ypai:a upda- an dysplasia: underlie ectodermal mutations hypohidrotic gene of EDA basis (2009). Molecular H. (2016). Stu- Feng, R. . Functional te. Koczorowski, . & (2016). . H., X., W. H. Zhang, Trzeciak, H., Feng, Wu, Y., . Gong, H., oligodontia. . 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No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. 10 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986548.85920515 — This a preprint and has not been peer reviewed. Data may be preliminary. 11