Posted on Authorea 20 Aug 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159795444.47623737 | This a preprint and has not been peer reviewed. Data may be preliminary. ydoi ae fhmpii n obdoeiydet otgosgn eein on deletions contiguous Radic* to Pamela extensive Claudia due and obesity bioinformatics mining morbid by data associations and clinical phenotype-genotype B unsuspected hemophilia Xq26.3-q27.2: of cases X- Syndromic characterize regions. to genomic importance involved the the highlight of linked findings associations (experimentally functional Our CXorf66 unveil and phenotypes). FGF13 to previous to 3 syndromes a OB similar all deletion SGDD, confirmed with pitu- with and approaches GH and HPO-connected associated in bioinformatic/statistical atresia POMGNT1, roles Our HPO anal additional to suggesting abnormalities, those MAGEC2. OB extra-phenotypic in gene, two and SOX3 showed of extra-deleted involvement CXorf66) case#2 one Only FGF13, and STRING-associations hypothyroidism, (10/119). (SOX3, significant SGDD itary highly and revealed (36/923) deleted GH approaches common (20/343), Bioinformatic/statistical case#1/#2 of between Xq26.3-q27.2. estimation 1- (P[?]0.00115) on and and 0.16-4.34-Mb databases genes involving networks) deletions additional mining interaction F9 al- 17 data complete (-protein showed strategies included STRING (cases#3-case#1) walking analyses Patients OMIM, STS Whole Bioinformatic/statistical Expected-values. Ontology), case-specific null-hypothesis-based (GH). Phenotype breakpoints. and basis hypotonia (Human SNP-array deletion molecular generalized Dense HPO the the and HB. of in Analyze (SGDD) with characterization delay probands and Aim: developmental hemizygous amplification global 3 lowed relationships. encompassing severe in causal deletions (OB), detected new hemizygous obesity were HB, suggesting that F9-deletions of showed extra-phenotypes cases literature express syndromic The may of genes F9-variants. vicinal pathogenic and with F9 associates (HB) B Hemophilia Abstract 2020 20, August 5 4 3 Paz 2 1 Bonduel Lapunzina Pablo Radic Pamela mining data extensive clinical and bioinformatics by unsuspected associations to phenotype-genotype due Xq26.3-q27.2: obesity on morbid deletions and gene contiguous B hemophilia of cases Syndromic Affiliations: Bonduel** Nevado optld eiti rfD unPGraa evcod eaooi Oncologia y Hematologia de Servicio Garrahan P Juan Dr Prof Pediatria Oncolog´ıa Hematolog´ıa de y de Hospital Pavlovsky. Servicio Alfredo Garrahan Hemofilia P la Fundaci´on Juan de Dr Pediatr´ıa Prof de Hospital La Universitario Hospital (INGEMM)-IdiPAZ, Gen´eticaMolecular M´edica de y (IMEX-CONICET/ANM) Instituto Experimental Medicina de Instituto 2,3 5 al Lapunzina Pablo , 4 n alsD Brasi De Carlos and , alsDne eBrasi** De Daniel Carlos , 1 aoaoi eGneiaMlclrd aHmfii GH,Isiuod eiiaExperi- Medicina de Instituto (GMH), Hemofilia la de Gen´etica Molecular de Laboratorio 1 iulAbelleyro Miguel , 2 areaSciuccati Gabriela , 1 iulMart´ın Abelleyro* Miguel , 2,3 areaSciuccati Gabriela , 1 1,6 1 ein Ziegler Betiana , 3 ail Neme Daniela , 4 1 ail Neme Daniela , ein Ziegler Betiana , 1 1 aiaMarchione Vanina , 4 iin Rossetti Liliana , 5 iin amnRossetti Carmen Liliana , 1 aiaDneaMarchione Daniela Vanina , 1 1 uinNevado Julian , Mariana , 1 Mariana , 1 Julian , 2 , Posted on Authorea 20 Aug 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159795444.47623737 | This a preprint and has not been peer reviewed. Data may be preliminary. rqetyfudi eohlaB(B MM360) hc soitswt eet ntefco Xgene IX factor the in defects are with hemorrhages, associates which prolonged OMIM:306900), or (HP:0005261), (HB, spontaneous hemarthroses B ( with hemophilia as in characteristics associated found clinical (HP:0005261) frequently (HPO), hemorrhage Ontology joint Phenotype spontaneous Human to According INTRODUCTION regions. matics. genomic involved the of X-chromosome Keywords: characterize associations to functional importance unveil the highlight to findings to syndromes Our similar deletion phenotypes). SGDD, 3 all and with of GH HPO-connected involvement in previous atresia roles a anal ditional confirmed abnormalities, approaches extra-phenotypic bioinformatic/statistical two gene, Our showed extra-deleted case#2 one Only and hypothyroidism, (10/119). pituitary and SGDD and (36/923) GH ( between genes (P[?]0.00115) deleted common STRING-associations case#1/#2 significant highly revealed approaches Bioinformatic/statistical Xq26.3-q27.2. STRING on OMIM, Bioinfor- complete Expected-values. Ontology), showed breakpoints. null-hypothesis-based (cases#3-case#1) Phenotype of deletion Patients (Human estimation the HPO and databases of in networks) characterization mining interaction data (protein-protein and included amplification analyses allowed matic/statistical strategies walking STS delay developmental global severe (OB), Whole obesity (GH). HB, of hypotonia cases generalized syndromic and of (SGDD) basis molecular the Analyze Aim: Argenti- (1425), Aires pathogenic encompassing with associates Buenos (HB) B Hemophilia 3081, Melo Summary de 0000-002-3901-3904 ORCID: Pacheco Radic Pamela Medicina. Claudia de Nacional na. Academia to: ratory, authors. correspondence co-senior as Address equally contributed CDB and authors. MB co-first ** as equally contributed MMA and *CPR matol´ogicas Spain; Garrahan Madrid, Aut´onoma,CIII, Universidad Paz, Spain; La Argentina; Universitario Madrid, Aires, Hospital Buenos (INGEMM)-IdiPAZ, (ANM)), Molecular Medicina Gen´etica M´edica de y Nacional CONICET-Academia (IMEX, mental otedltrosntr ftecuaiegntcvrat(jrln-ofe l 09.Hwvr dissimilar However, 2019). related al. closely et is (Tjarnlund-Wolf (1–5%) FIX:C, variant moderate accompanying genetic its causative (<1%), and the severe severity, of in phenotypic nature HB clinical deleterious of the the classification which to in permits (5-40%), (FIX:C) mild levels human and activity most with FIX occurred plasmatic as The genome-wide defects HPO. gene obesity to of and hundreds according (HP:0002023) with diseases atresia associated anal each (HP:0011787), are hypothyroidism (HP:0001513) central (HP:0001290), hypotonia ized F9 [email protected], MM304) oee,ciia hrceitc sdvlpetldly(P0023,general- (HP:0001263), delay developmental as characteristics clinical However, 300746). OMIM , F9 (HPJG); dltoswr eetdi eiyospoad ihH.DneSParyadcase-specific and SNP-array Dense HB. with probands hemizygous 3 in detected were -deletions ain .Castex R. Mariano eohlaB bst,svr lbldvlpetldly ydoi q7dltos bioinfor- deletions, Xq27 syndromic delay, developmental global severe obesity, B, Hemophilia F9 3 IEE,Cnr eIvsiaio imeiae e eEfreae aa,IS- Raras, Enfermedades de Red en Biom´edica Investigaci´on de Centro CIBERER, n iia ee a xrs xr-hntpssgetn e aslrelationships. causal new suggesting extra-phenotypes express may genes vicinal and 5 udc´ nd aHemofilia la Fundaci´on de 4 evcod eaoo´ayOclgı,Hsia ePediatr´ıa de Hospital Oncolog´ıa, y Hematolog´ıa de Servicio 414080,Et:261. Ext.: 48058803, 5411 IHM,AM,Beo ie,Argentina. Aires, Buenos ANM), (IIHEMA, SOX3 lui aeaRdc oeua eeiso ampii Labo- Haemophilia of Genetics Molecular Radic, Pamela Claudia , FGF13 FGF13 F9 F9- lrd Pavlovsky Alfredo eein novn .643-bad11 diinlgenes additional 1-17 and 0.16-4.34-Mb involving deletions ains h ieauesoe hthmzgu deletions hemizygous that showed literature The variants. , CXorf66 and 2 CXorf66 MAGEC2 n hs P soitdwt B(20/343), OB with associated HPO those and ) (FHAP); eprmnal ikdto linked (experimentally . 6 nttt eIvsiainsHe- Investigaciones de Instituto SOX3 nO ugsigad- suggesting OB in rf rJa P. Juan Dr Prof. POMGNT1 2 nttt de Instituto , Posted on Authorea 20 Aug 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159795444.47623737 | This a preprint and has not been peer reviewed. Data may be preliminary. h rtya flf n hscleauto lorvae GDadG.Atalo hri hormones thyroid of trail A GH. and SGDD since revealed OB also developed evaluation He HB. physical performed months severe was and 8 with surgery At life diagnosed The observed. subsequently of (AA). were was atresia year complications he anal bleeding evaluation first of no preoperative the and because a hemophilia birth in the of his age was abdominal diagnosis after of He urgent a underwent hours pregnancy. neonate of 12 The knowledge uncomplicated town hemophilia. without an local of after history his family delivery in no vaginal with surgery by parents unrelated born of weight son IU/dL. only years-old birth 103 3 normal of meningitis, at activity with to died FIX neonate a boy related shows The sequelae mother follow-up. Severe Case#2 proband’s his The during karyotype. pneumonia. observed male aspiration were (SGDD) to (OB) normal hemorrhage delay due obesity developmental cerebral had severe global and developed He severe ischemic He revealed (GH). also arterial hemophilia. evaluation hypotonia pregnancy. of physical uncomplicated history and generalized an family life and after no of delivery months with phenotype. vaginal first parents bleeding by the unrelated mild born since of weight a son birth presented the normal patient inhibitor was with The or He neonate without reactions days). term HB allergic exposures a of severe was 50 severe history with He than No without transformation, diagnosed (less given. observed was performed hemorrhagic were was he was concentrates development extensive laboratory, IX craniotomy Factor an new decompressive plasma-derived a and with emergency inhibitor, after An artery Postoperatively, cerebral herniation. complications. bleeding cerebral middle and left edema the cerebral to of due stroke meningitis ischemic to secondary hypertension outcomes Case#1 and features a clinical and cases. (Res.215/96-April/2007) Report: all Case study from this obtained approved was (CEIANM) the consent of informed Committee exons written Ethical eight institutional all local of Our amplification PCR 1991). of lack al. a et showed (Lahiri study this in included F9 HB severe with Patients samples and populations Studied entire METHODS of AND of cases MATERIAL correlation all databases, comprehensive virtually genotype-phenotype available a reviewing using allowed and manifestations events clinical associations these specific gene-gene of large their showing definition with HB extents molecular severe genetic precise with their The patients three obesity. in morbid event and pathogenic symptoms the all bleeding characterize 1990). encompassing showed to was only al. deletions work et patients et this others Stoof Koeberl of while 2016; aim 2016; 2014) The al. al. al. et et et Jourdy (Nakamura hypotonia, Alatzoglou 2014; HB stature, 2007; with al. short associated al. et associated scoliosis, et Hewitt those entire Vencesla seizures, 2016; the 2018; from hypopituitarism, al. of al. different et (ID), rarely (Nakamura deletions abnormalities disability cryptorchidism are with phenotypic intellectual bilateral they overweight, patients as additional but such reported patients presented HB, some hemizygous Xq26-q27 with in However, on detected level. genes only are sequence vicinal deletions the in large But at most characterized 1994). 1999). reasons al technical al. et to et (Ketterling Due uncommon Thorland are 2018; deletions al. gene cases et complete HB Santoro while and complete and 2013; with treatment 2010). patients al. patient’s the 1.4-11.7%, for et al. ranging complication in et frequencies important variants (Santagostino an inhibitor family is genetic show same (inhibitors) identical FIX the entire exogenous with of against with patients probands cases in in all described reported Nevertheless, were phenotypes been bleeding have discordant phenotypes HB clinical eoi-N a bandfo eihrlbodluoye sn tnadsligotmethod out salting standard a using leukocytes blood peripheral from obtained was Genomic-DNA . -ot-l o a rnfre oteItnieCr nto h PGfrsvr intracranial severe for HPJG the of Unit Care Intensive the to transferred was boy 7-month-old A . erodbywstaserdt PGfrclsoycoue ewsa3 ek’gestation weeks’ 36 a was He closure. colostomy for HPJG to transferred was boy year-old 2 A . F9 xn n iia ee ofiuigcmlxsnrmccsso hemophilia of cases syndromic complex configuring genes vicinal and exons F9 eein hwdFXC1.Dvlpeto niioyantibodies inhibitory of Development FIX:C<1%. showed deletions tetccu pneumoniae. Streptococcus 3 F9 F9 si othmngns ohpartial both genes, human most in as , eein eotdi h literature. the in reported deletions F9 eein a hw>0 (Radic >20% show may deletions eriaigdtce arterial detected Neuroimaging F9 F9 e.g., , and Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. bomlte n oantt h itdpnlo soitdgns(//hpo.jax.org/app/). genes phenotypic classify associated precisely of to panel (GenBank accessed listed Genome was the Reference HPO annotate the to 2017). to and Dunnen (dem abnormalities mapped (HGVS) was Society breakpoint Variation Laser- deletion Genome Star NC 3’ (DNA 7.1 and ChrX: SeqBuilder 5’ using GRCh38.p13, characterized performed were Each annotations primer gene). and analysis sequence DNA analysis Most statistical to and designed mining primers data and conditions. genotype-phenotype Argentina) thermal-cycling Thermal-Cycler Bioinformatics, (Promega, a and Polymerase in reagents ST1) DNA standard Table Taq (Supplementary applying Go sequencing (Germany) Sanger of Biometra by U junctions Thermal- 1.5 breakpoint the using a characterize input in gDNA ST1) of Table 0.6 ng (Supplementary with manufacturers. breakpoints gap-PCR USA) the size deletion by Biosystem, Standard (KAPA recommended 3’ Polymerase conditions and under DNA 5’ (China) Range inferred BIOER Long the Cycler KAPA by of located U primers 0.75 4 using or breakpoint input 3 deletion gDNA of each (LR-PCR) range-PCR (encompassing) Sets Long SF1; bridging Figure performed experiments. (Supplementary was SNP-array SNP-array of Gap-PCR the interval junction. SNP from deletion ST1). positive-negative each obtained each Table of from delimitation results Supplementary used a the were refine pairs to account divided Consortium applied primer SNP Reference into and a Genome designed taking were for upon (STS) breakpoints, value based sites R were tagged frequency normalized sequence positions allele (GRCh38.13). observed Case-specific genomic an 13 the All release addition, of patch In SNPs. 38 ratio specifications). Build all 2) manufacturer’s Human for (base (under used applied log value metric was The the R analysis CA). is normalized Diego, which expected San ratio the for (Ilumina, by Studio R Standards Genome log (International in the San contained analyzed ISCA were was tool data (Illumina, Viewer from Image Chromosome chromosomal specifications Consortium). defined the Microarray for manufacture’s using Cytogenomics regions coverage ( enrichment the CCMC large and specific according Arrays) and (95%), Cytogenomic conducted centromeres generally and was and 1SNP/2.5Kb SNPs cytobands/telomeres genome- is A tag Resolution CA). Diego, CA). 850,00 San Diego, (Illumina, of CytoSNP850K scan large platform the the detect wide using within to performed, region was analyzed analysis autosomal was SNP-array uninvolved product each an of using reference identity amplification control size multiplex molecular in and deletions presence/absence The 2013). relevant All of levels 1. Table FIX:C characterization showed in genotype summarized sister Molecular are one cases and all B, studied, of hemophilia not characteristic severe was Clinical with other brothers the two and has inhibitor patient IU/dL. presented FIX The age, and 10 developed management of disability. them recommended months walking the of 7 severe receive one At with not did hemiparesis concentrates. but right FIX hemorrhage plasma-derived a system severe therapeutic nervous central to to had IU/dL. due days he 95 later exposures The month of 50-100 one FIX:C after inhibitor. died a BU/mL) transient shows boy concentrates UB/mL) mother The IX proband’s (<2 old. Factor The Case#3 years response plasma-derived 1/2 complications. low to 2 postoperative a was day to developed he related exposure when he sepsis presented 50 performed and patient was than reaction The closure more allergic colostomy Karyotype. After an male presented normal phenotype. he had bleeding He mild (PH). a hypothyroidism pituitary central confirmed ain ihsvr Bfo HPwodvlpdFXihbtra h g f3 er tte:22 (titter: years 30 of age the at inhibitor FIX developed who FHAP from HB severe with Patient . F9 locus eune eeaaye yPRapicto,acrigt ai ta Rdce al. et (Radic al et Radic to according amplification, PCR by analyzed were sequences . mlfiain agn 0-,0 pwr efre navlm f25 of volume a in performed were bp 700-2,100 ranging Amplifications : 0031) eei ain oecaueflostegieie fteHuman the of guidelines the follows nomenclature variant Genetic 000023.11). RPRapicto a efre navlm f25 of volume a in performed was amplification LR-PCR : 4 β- μ lbngn sa as gene globin ih50n of ng 500 with l μ ih300 with l μ F9 M Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. hssto 3cs#/2cmo ee ihtegn esHOascae ihec ftephenotypic the involves of analysis each STRING with that Co-expression, associated Given Co-occurrence, Fusion, HPO (n=343). 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(Table entire NC the and bp, involving q27.2; 4,339,584 deletions three interval; of all Xq26.3-q27.2 deletion of a characterization full showed permitted sequencing Supplemen- Sanger ST1, Table (Supplementary approaches SF1). using amplification Figure (case#1-case#3) PCR cases tary nested all in and/or junctions long-range breakpoint STS standard, each a bridging achieved of were up (Supplementary amplifications setting intervals Gap-PCR the amplifiable allowing PCR Xq27.1 to on breakpoints Mb deletion SF1). 0.165 the to Fig. further Xq27.1- case#3 delimitate on and to Mb Xq27.1-q27.2 4.33 strategy on walking about Mb to 3.9 deletion to case#1 case#2, narrowed 27.2, results SNP-array 12 nearby. regions all additional involved amplify to failed Patients variants structural the of aleatory characterization using Genotype coordinates GRCh38.p13 associated choosing (Ho) by null-hypothesis RESULTS set) of gene at with set (control genes pro- 100 associated a locations (//www.random.org). a picking significantly genomic numbers case) on not is based random syndromic or simulations deletion near a Monte-Carlo-like whether hemizygous or applying determine of the obtained to (part was in (E-value) order abnormality lost wasexpected-value In phenotypic function network particular gene interaction 2019). a a protein-protein al. between STRING et connection the (Szklarczyk posed gene-products, (//string-db.org/) between online relationships accessed the study To D1 SPANXB1 CDR1, case#3 6,2 pdlto,g.139,517,752 deletion, bp 160,027 a , , F9 case#2 LDOC1 and F9 stepiaycuefrthe for cause primary the is MCF2 ,0,8 pdlto,g.138,932,331 deletion, bp 3,904,082 a , , SPANXC F9 pcfi mlmr n N-ra tde eeldthat revealed studies SNP-array and amplimers specific ta r eee ntecs# hwn nyahmpii related hemophilia a only showing case#3 the in deleted are (that MCF2 0031:g.137,786,488 000023.11: , PNA,SPANXA2 SPANXA1, eeascae iha noei oeta,b noiga encoding by potential, oncogenic an with associated gene 5 3,7,7dl novn einwti chrXq27.1 within region a involving 139,677,779del, eue atrI activity IX factor reduced 4,2,7dl novn chromosome involving 142,126,072del, , 4,3,1dl novn chrXq27.1- involving 142,836,413del, FGF13 SPANXD , ATP11C , AE3 MAGEC1 MAGEC3, H:015) hc in which (HP:0011858), , CXorf66 F9 F9 . deletions vs Case#1 , SOX3 0.16), ) Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. hsapoc nysoe oncin ihP n Awe osdrn l yeo vdnebtit but evidence of connec- type weighted showed all analysis considering STRING The with when genes AA considered. genes), (HP:0008245) was and PH evidence PH between experimental tions with only when connections not be showed did may only PH to those approach to applied and 3). This similar was (Figure AA Ho/E-values analysis PH STRING GH, devised and comprehensive equally SGDD, AA a with with 1), OB, above link (Figure HB, performed genes approach severe deleted bioinformatic of including blind-connecting set case#2 entire the by of expressed consequence syndrome gene, complex associated the AA an with with POMGNT1, association scored 0.797 a showedATP6VOA2 approach This (n=343). OB with and (n=923) GH with (n=119), lations but SGDD to connections related STRING between genes of connections of investigation sets similar same the a chance. with approach, by the bioinformatic obtained on unbiased be only this focusing to refine unlikely phenotype to exceedingly shared order their are In with OB) associated and those GH and SGDD, gene-products (i.e., deleted features common case#1/#2 between tions significant highly These and with connected (HP:0001513) M&M, OB in indicated as and simulations computer with SGDD, by connected of considering calculated probability combined approach genotype-phenotype, a This connection estimated of deleted 2). degree common (Figure this case#1/#2 than connections the SGDD 3 with with (HP:0011344) tions [?] SGDD between and involved connections 2 genes the 1, the indicated interaction), considered evidence only (no all approach 0 first classifying the Homology) nections and Text-mining Databases, Experiments, ncs# eeinetmtn lblHo-based global a estimating deletion case#2 in STRING A AA. to genes 26 and PH to linked genes extra-gene 115 case#2 presents the database on HPO only focused 1). analysis (Table AA) and PH case#1, to (4.3 case#2 respect than gene deletion SF2). bigger Figure a encompassed (Supplementary case#1 #2 Although and AA #1 OB and cases PH clinical and expressed both (6/923) Case#2 deleted GH directly define is that (7/119), OB, genes SGDD with associated the with to associated connection genes CTNNB1 three, their the another of (SGDD-GH-OB); with genes, despite HPO 13) Interestingly, three genes of deleted genotypes, SF2). common out cases’ the Figure (6 between (Supplementary connections #2 (9/343) of by and map obtained cases#1 comprehensive be a to of showed expected STRING not all-evidence are deleted The features shared phenotype common #2 three and their case#1 with chance. associated between those interactions and experimentally-demonstrated genes associated STRING Ho of the magnitude Again, features. clinical three SPANXC CXorf66 POMGNT1 ATP11C and xeietlylne to linked experimentally score ( score CNKSR2 6/0)etmtn obndH rbblt ae nrnons of randomness on based probability Ho combined a estimating (67/100) 810 ofiuigacmie rbblt ae nH of Ho on based probability combined a configuring (8/100) SOX3 FGF13 (22/100), ( ?077 siaiga estimating [?]0.797) score xeietlevidence experimental .4)( 0.546) CXorf66 210 ny2i 0 admycoe ee eefudt hweulo oeconnec- more or equal show to found were genes chosen randomly 100 in 2 only (2/100, SOX3 (4/100), r eae oO n H and GH; and OB to related are , MAGEC2 P .9)( 0.797) grs( figures P SOX3 ), ihaSD soitdgene associated SGDD a with ZIC3 00)etmtn global a estimating =0.09) NTRK2 FGF13 POMGNT1 P SOX3 (0 FGF13 Fgr ) n xrse w diinlpeoyi bomlte (i.e., abnormalities phenotypic additional two expressed and 1), (Figure =0.06), n oascainwt n Hgn Fgr ) nesadn that Understanding 3). (Figure gene PH any with association no and P < CXorf66 /0)and 1/100) < (18/100), FGFR3 P 510 and (5/100) , .02 niae htotiigsc ereo TIGinterac- STRING of degree such obtaining that indicated 0.0012) OTX2 Fgr )wsapidt nlz h aesto 3dlto genes deletion 13 of set same the analyze to applied was 2) (Figure (exp.SGDD) (6/100), SOX3 P FGF13 siaiga estimating ihahg evidence high a with SD) .04 h aeaayi ihG (HP:0001290) GH with analysis same The 0.0004. (SGDD)= , MAGEC2 P and ATP11C P HESX1 with CDR1 P) .005(iue3.Tesm nlsswt AA with analysis same The 3). (Figure 0.000005 (PH)= SOX3 siain ( estimations fudi igecnrloto 0 admypicked randomly 100 of out control single a in (found 6 CXorf66 POMGNT1 < ATXN1 2/0)aogtesto 5gnsencompassed genes 15 of set the among (22/100) POU1F1 .1 h aeaayi nG associated GH in analysis same The 0.01. P and P (11/100), niae nyamds igedrc association direct single modest a only indicated (31/100), POMGNT1 epO) .3 ti neetn ont that note to interesting is It 0.03. (exp.OB)= epG) .034 nOB, In 0.000324. (exp.GH)= MECP2 4/0) h oascae ihobtaining with associated Ho The (40/100). vs ( P score r eae oaltrepeoye by phenotypes three all to related are , score . b,telte novda additional an involved latter the Mb), 3.9 oSD n H while GH, and SGDD to , exp. ATP11C CXorf66 r eae oSD n B two, OB; and SGDD to related are , .5)( 0.750) < ihasoe077(o /0 simu- 0/100 (Ho: 0.797 score a with P saHOascae eewt all with gene HPO-associated a is , .5 niae htteobtained the that indicated 0.05) G) .074 h nlssof analysis The 0.000754. (GH)= (51/100), (64/100), P 00)and =0.06) MAGEC3 P MAGEC3 G) 0.00115. (GH)= CXorf66 number ATP11C SOX3, (51/100) (66/100) CXorf66 showed fcon- of gene a with Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. lhuhi a eetalc fadtie n ytmtcciia igoi fsnrmcptet bearing patients syndromic of diagnosis clinical systematic partial and and detailed al. scoliosis a SF3). et adding of Figure lack (Supplementary ID (Hewitt overweight a and al or reflect seizures obesity et may suffering expressed it Hewitt of Although region, evidence and studied not 2016) was the entire there in the but al. genes targeting hypopituitarism et deletions all obesity (Nakamura large them spanning of one al on deletions none and et but genes four Nakamura acquisition, reported several speech 2014) delayed encompassing SF3). and walking) cases Figure (late to three entire DD (Supplementary up school hypotonia, and the stature, least special walking); short including at (ID), needs, (late deletions reaching disability (DD) five region intellectual delay downstream reported mild developmental 2016) scoliosis, and cryptorchidism, needs al. bilateral et hypotonia, (Jourdy overweight, al from involving 2014). et them et al. 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(Nakamura SF3) et Figure Jourdy entire (Supplementary 2014; all phenotypes al. observed compiling highlighting the evidence about impacting conclusions literature roles similar the reaches key Xq27.2 of to analysis Xq26.3 from detailed expanding and comprehensive a Notably, significant more a even estimated obnto GDG-Betmtn ihysgicn association significant highly a randomness, estimating on SGDD-GH-OB Ho-based combination the and deletion gene genes the connected (HP:0002023) infiatascain ihSD ( among two of SGDD deletion on interactions with combined attention the associations main of of significant the probabilities number the focus of phenotypes the estimation expressed allowed others: weighting common the the work phenotypic over and these genes this genes and of deleted each #1 in common with cases case#1/#2 associated performed our HPO SF2). by analysis genes Figure expressed of (Supplementary Bioinformatic/statistical number genes phenotypes a deleted common and statement common main OB) case#1/#2 later indeed three accurate and this and entities the hindering to GH symptoms among Related SGDD, and relationship (i.e., characteristics. diag- signs #2 HPO phenotypic clinical of tight and precise plexus the losses on composite is based function intricate was defined an patients between as the dissections express in cases abnormalities syndromic reported phenotype noses, not of has classification HPO literature Although the sources, median the different a involving from year, et deletions (Beltran-Miranda efforts per by phenotype. hemarthoses search episodes caused one comprehensive HB bleeding than the of fewer less cases Despite or and two IU/kg 2005). as 500 defined than al. phenotype lower consumption bleeding concentrate mild lifelong a expressed per- #2 and loss FIX:C genetic ap- the databases. bioinformatic-statistical with of and of Inconsistent determination networks use protein exact extensive accessible the the publicly on allowed and based events proaches correlations deletion genotype/phenotype the reliable of mitting objectives. characterization genetic has desirable sequence walking probands, all The STS hemizygous cover in case-specific to breakpoints capable analysis, deletion be SNP-array the to of including proved characterization approach, amplification-based practical gap-PCR entire and applied by available caused HB widely severe The with patients three of characterization molecular full F9 a showed study present The DISCUSSION 3). (Figure 0.002 (AA)= eein n otgosgenes. contiguous and deletions FGF13 FGF13 to < % omlyascae ihsvr B(.. u yia ae3,css#1 cases case#3), typical our (e.g., HB severe with associated normally 1%, SPANXN4 and P SOX3 FGF13 =0.00012. P 001,G ( GH =0.001), including Fgr ,SplmnayFgr F) oevr u approach our Moreover, SF2). Figure Supplementary 2, (Figure SPANXC (4/100), F9 SOX3 n oeajcn eaae,epesn idbleeding mild a expressing megabases, adjacent some and SOX3 7 SOX3 P xrsigmsl eeet idI,seilschool special ID, mild to severe mostly expressing eeinascae u nig ihtephenotype the with findings our associates deletion 007)adO ( OB and =0.0072) and 1/0)and (12/100) MAGEC2 F9 SOX3 epciey w fte,woshowed who them, of two respectively; , and P MAGEC2 mn te ee n expressed and genes other among < P FGF13 .04 whilst 0.0004, 006) ouigo single on Focusing =0.0066). 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Data may be preliminary. ito n vnulypeeto ftefl xrsino eei iodr rmtemr ento fa of definition mere the from disorders genetic of pre- expression improving X-linked full ultimately characterized the databases, fully of public of prevention enrich cases eventually to syndromic and information of diction indispensable report with clinical contributes detailed of deletions the involvement considerations, probable these the Beyond show to atresia. able anal been and has all dism approach considering practical well- information our single mined SOX3 cases. sense, a the syndromic broader and of this all loss characteristics In gene combine meaningful clinical single to and achieve a elements) necessity to between genetic the of shortcut associations (and drawback highlights univocal genes a intrinsic get feature, as an with to phenotypic However, used difficulty databases abnormalities. defined the be phenotypic public about may and from approach, losses likelihoods information the function hypothesis the gene null combining between approach of associations evaluation practical 3). our statistical (Figure that the genes revealed AA-related Taking with findings 2011). interactions Our al. showed et genes, and deleted (Chung database, and all HPO development diseases and the midline heart features in axial congenital clinical both complex all account Xq26.3-q27.3. in central and malformations, into heterotaxy, stages on hindgut anomalies, and earliest regions urogenital system the vicinal foregut, nervous the in to of required development mapping specification, factor asymmetry both left-right indicated transcriptional 3) analysis a (Figure STRING as Moreover, family) described majority, states. protein a disease of (ZIC) of regulation and cerebellum testis the pathways, in in signaling involved ligases co-expression be processes, ubiquitin-protein to a cellular known E3 all, is finger-containing Pathway not zinc Cascade if RING-type Ubiquitination 2010). of al. deleted activity and et ligase the (Doyle GH ubiquitin including OB, enhance members, to to added family shown PH, gene and MAGE AA All (i.e., gene, features deleted between clinical additional extra-HB association one five with only of associated and set dystrophies SGDD) entire muscular the of expressed cases Case#2 some and eyes, that and disorders in brain, inherited mutations muscles, to pathogenic the related of been development has affect 1) N-acetyl-glucosaminyl-transferase mannose gene O-linked deleted (protein the 2002). STRING, al. from POMGNT1 et obtained Laumonnier evidence 2014; to al. According et (Alatzoglou of in cases variants pattern some whilst expression in development delay The pituitary and 1996). neural al. during et processes Gedeon 1993; that al. (BFLS) et syndrome Borjeson-Forssman-Lehmann al. the et example, the For Anson chromosome. includes X 2014; human the al. of et region Wu 27 2016; reported al. Nakamura et Several and Jourdy (e.g.,Wu 2016; literature al. the et with (Nakamura 1988). concordance SF3) in Figure Supplementary phenotype cases, additional 2013). no full al. with and et case#3, features the DeStefano our involving 2007; HB, deletions with al. smaller et associated association, logical Xiao the 2007; to al. (Mu˜noz-According et growth Nishimoto hair 2001; and al. number, that vesicle et suggestions neurotransmitter Sanjuan persistent presynaptic been differentiation, have neural There development, Nakamura 2019). and from OB al. evidence between et the linkage causative conditions, severe the other support OB/ and not HB do severe cases expressing Hewitt region and this in deletions large FGF13 , loci CXorf66 epnil o etldsreswr ecie,fo hs hthv enmpe oteXq26- the to mapped been have that those from described, were disorders mental for responsible xeietlmrn oesdmntae that demonstrated models murine experimental , hc sHOrltdt GD BadG Fgr ,SplmnayFgr SF2). Figure Supplementary 2, (Figure GH and OB SGDD, to HPO-related is which , SOX3 n AEfml ee noeiy eeomna ea,hptna iutr hypothyroi- pituitary hypotonia, delay, developmental obesity, in genes family MAGE and eeinsoe lnclsmtm fml-oeaeitleta adcp(Stevanovic handicap intellectual mild-moderate of symptoms clinical showed deletion MAGEC2 POMGNT1 MAGEC2 ihP rA,sm ugsieosrain hudb ae noaccount. into taken be should observations suggestive some AA, or PH with fe rsne ihmna eadto Mruie l 2009). al. et (Mercuri retardation mental with presented often n nA-eae gene, AA-related an and F9 n partial and MAGEC2 8 SOX3 MAGEC2 MCF2 FGF lhuhHOdtbs i o eeladirect a reveal not did database HPO Although . SOX3 FGF13 a ietyascae ihP-eae genes PH-related with associated directly was eefml a rae oe ncraniofacial in roles broader has family gene CXorf66 ZIC3 eeinepesdol Brltdclinical related HB only expressed deletion a soitdwt omlphysiological normal with associated was F9 , SOX3 osascae ihwih an(Sinden gain weight with associates loss MAGEC1 n io xesosnab r only are nearby extensions minor and amme fteZn ne fthe of finger Zinc the of member (a FGF13 seprmnal soitdwith associated experimentally is eeascae ihintellectual with associated were uprigteassociation the Supporting . and MAGEC3 POMGNT1 ee,were genes, ZIC3 FGF13 was , Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. eenA,Kza M oisnH ii ,Shesne ,Tre ,Mle C(96 enmn of Refinement (1996) JC Mulley Syndrome. Borjeson-Forssman-Lehmann G, for Turner Localisation D, Gene Schlessinger and Xq26-q27 of G, of family Pilia Map Genetic a H, Background comprise Robinson the HM, complexes 10.1016/j.molcel.2010.08.029. Kozman protein MAGE-RING AK, doi: (2010) Gedeon 39(6):963-74. PR Cell Potts Mol M, ligases. Proc Yang AM ubiquitin J, Hypertrichosis. Wang Christiano E3 Generalized J, JC, Gao Salas-Alanis Congenital JM, 10.1073/pnas.1216412110. R, X-linked Doyle doi: Cepeda-Valdes With 7;110(19):7790-5. V, Cirulli USA Associated Jobanputra D, Sci FGF13 M, Warburton Acad Shirazi B, Biol on Natl Y, Levy Effect Mol Shen M, Position Tadin-Strapps X, Methods (2013) M, Sun to Nomenclature. Kurban Y, VACTERL-H L, Han HGVS Petukhova ET, From KA, Using Fantauzzo doi: (2011) Variants GM, DeStefano 2011;155A:1123–8. D Sequence Genet Describing Chitayat 10.1007/978-1-4939-6442-0 Med (2017) B, doi: 1492:243-51. J JT Casey Dunnen Am J, den disorders. 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Curry craniopharyngeal MT 1160. the Dattani F, of H, Ryan persistence Stewart N, with P, Thomas Rogers D, the A, Saunders of Azriyanti aspects KS, all for Alatzoglou accountable be to agree REFERENCES and and submitted data, as supervised manuscript and final work. coordinated the study, approved content. authors the intellectual All designed important and for manuscript. manuscript the conceptualized the revised Brasi reviewed and De critically reviewed collection and and data analyses, the Bonduel initial designed Drs the Rossetti out and carried Neme data, Sciuccati, Lapunzina, collected Nevado, instruments, Marchione, reviewed Drs and Ziegler, manuscript, MSc initial the drafted manuscript. study, the the designed revised and and conceptualized Abelleyro and Radic Drs Statement: Contributors’ participate: to Consent April/2007). approval: Ethics Disclosures: the Interest (CONICET), of Council Conflict Research Hemophilia. of National Federation Word the Promoci´on the Foundation, Cient´ıfica de Tecnol´ogica and Nacional y Fiorini (ANPCyT) Agencia Florencio the Foundation, Roemmers Funding/Support: work. this of phases different Acknowledgements: genotype. characterized properly u oa ntttoa tia omte CIN)apoe hssuy(Res.215/96- study this approved (CEIANM) Committee Ethical institutional local Our hssuywsspotdb rnsfo h e´ a´nFudto,teAbroJ. Alberto Ren´e the Bar´on Foundation, the from grants by supported was study This h uhr hn iuld eao it n it enrfrterkn epin help kind their for Hepner Mirta and Pinto Tezanos de Miguel thank authors The rte nomdcnetwsotie rmalcases. all from obtained was consent informed written A h te uhr aen xml oflcso neett disclose. to interest of conflicts example no have authors other The 17. 9 Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. tvnv´ ,Lvl-ag ,ClinnJ odelwP 19)SX sa -ikdGn eae to Related Gene X-linked an Is SOX3 2013-8. (1993) 2(12): X-linked PN Genet the Mol Goodfellow of Hum J, Knockout SRY. Causes Collignon (2019) In- and R, GS Fat (2018) Lovell-Badge Brown Pitt 10.1096/fj.201901178R. Stevanovi´c to M, DE, A doi: Output Cohen Tagliaferri Sympathetic 33(10):11579-94. 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Thorland C, the TJ, 14(10): Negrier in Lind Haemost V, EL, Thromb Vielhaber J Gay RP, disability. microarray: C, Ketterling intellectual cytogenetic Zawadzki by in characterized gene S, deletion SOX3 F9 Meunier the complete with M, of patients Fretigny role six of ML, Study (2016) Carage C B. N, Vinciguerra haemophilia with Chatron patient Y, a in Jourdy chromosome Molec- X (2014) 10.1111/hae.12395. human RT the Macgillivray doi: JK, of Wu deletion 20(3):e230-4. LD, bp Wadsworth Haemophilia 4,409,480 SL, Yong a VC, of Smith characterization LA, ular Brown EM, Chou J, Hewitt 10.1002/(SICI)1096-8628(19960712)64:1 doi: 12;64(1):63-8. S. Genet Med J Am 10 < 63::AID-AJMG9 > 3.0.CO;2- Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. iue3 etmpsoigtesm TIGbsdaayi fFgr u associating but 2 Hypothy- Figure Pituitary of of used. analysis genes are Ontology connections based (HP:0002023). STRING Phenotype Atresia of STRING Anal Human same and with (HP:0008245) the (n=14) roidism showing genes map deleted case#2 Heat phenotype. given the 3. with Figure associated genes all Phi, by capital divided (Greek Enrichment connection Functional Del and genes; Networks indicates connected ( Interaction evidence circle) tion (Protein-Protein highlight (open arrows database Exp a black STRING by Gener- Analysis); the (characterized (HP:0001513). (HP:0011344), common in Delay #2 row; Obesity item Developmental and upper open and evidence Global Case#1 genes, interaction, (HP:0001290) Severe deleted box). (no i.e., Hypotonia 13 (closed HPO, 0 encompassing alized [?]3 by classifying: regions and classified share connections gray) abnormalities deletions) (dark of phenotype hemizygous 2 number of gray), the region pale abnormalities. with common connection, phenotypic correlates (1 common gradient 1 their gray box), with deleted the associated common black, HPO case#1/#2 to between genes interactions the based and STRING genes showing map Heat FIX:C the 2. Obesity; on Figure OB: areas Hypotonia; rectangle Generalized grey as GH: depicted Delay; Developmental are < Global cases Severe between (i.e., features SGDD: clinical background; genes Shared relevant shown. Most are boldface. in (GRCh38.p13) in names highlighted (official are genes , coordinates of representation breakpoint’s graphical Deletion panel: below. Xq26- Lower on (case#1-#3). series genes cases our italics presented intervenient from three all deletions the large including of characterized region of reference extent the q27 showing Scheme Trans- doi: 1. Figure 34(3):366-77. Synaptic Neurosci Hippocampal Cell Impaired Mol (2007) 14. DM LEGENDS Factor Ornitz Growth S, Fibroblast Feng Lacking K, Mice Yamada 10.1016/j.mcn.2006.11.020. in F, Plasticity in Laezza and deletions F9 L, mission large Xu of 10.1160/TH13- M, Characterisation doi: (2104) Xiao 2;112(3):459-65. X Wang Haemost H, Thromb Wang B. X, haemophilia Xi severe J, 12-1060. with Dai G, patients You unrelated Q, seven Ding Y, the Lu of X, deletion Wu complete a quantita- real-time of and diagnosis 10.3324/haematol.10693. Marker carrier (2007) doi: B EF 92:1583–4. hemophilia Tizzano M, confirm Baiget to M, analyses Quintana tive 10.1111/hae.13804. M, Baena doi: MJ, 25(4):567-574. Barcelo Haemophilia A, Vencesla IX. factor Key coagulation J, of patients: Westman biology B D, underlying haemophilia 5:101–5. Dimichele in Haemophilia MA, therapy risk. replacement Tj Koerper highest IX A, the factor confer Shapiro to deletions I, response with gene Anaphylactic Warrier complete networks (1995) JM, SS association Lusher Sommer protein-protein Acids JB, NS, Nucleic Drost v11: EC, datasets. STRING Thorland 10.1093/nar/gky1131. experimental Morris (2019) doi: genome-wide NT, Doncheva C in D607-13. M, discovery Mering 47: Simonovic functional Res J, von Huerta-Cepas supporting LJ, S, coverage, Genet Wyder Jensen increased Mol A, P, Junge F9. Bork D, the Lyon JH, encompassing AL, B Xq26.3q28 Gable Hemophilia of D, (2018) deletion Szklarczyk FWG 10.1002/mgg3.425. a Leebeek by doi: AJA, caused 6(6):1220-4. Kievit disability Med MJHA, intellectual Genomic Kruip with FAT, female Vries a de in R, Kersseboom SCM, Stoof MCF2 % eue atrI ciiy eeeHmpii ;A:Aa tei;P:PtiayHypothyroidism. 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. neln hsdrc oncinbtenMGC n I3(nAa tei ikdgn) oexperimental No gene). linked found. Atresia Anal were (an connections ZIC3 STRING and MAGEC2 evidence-based between connection direct this underline 12 Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. 13 Posted on Authorea 20 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159795444.47623737 — This a preprint and has not been peer reviewed. Data may be preliminary. data-mining unsuspected-phenotype-genotype-associations-by-bioinformatics-and-extensive-clinical- of-hemophilia-b-and-morbid-obesity-due-to-contiguous-gene-deletions-on-xq26-3-q27-2- 2.docx Table file Hosted data-mining unsuspected-phenotype-genotype-associations-by-bioinformatics-and-extensive-clinical- of-hemophilia-b-and-morbid-obesity-due-to-contiguous-gene-deletions-on-xq26-3-q27-2- 1.docx Table file Hosted vial at available at available https://authorea.com/users/334229/articles/476235-syndromic-cases- https://authorea.com/users/334229/articles/476235-syndromic-cases- 14