Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. uuQi Muyu Atresia BMPR2 Pulmonary Pathogenic Novel in Variant a Identifies Sequencing Exome Whole h orsodn uhro hsarticle. this China, of author Shanghai, corresponding the District, Funding: Putuo Road, counts: , word Luding Separate Cardiac of of title: 355 Department Running of words: Director No. Key Professor, Shanghai, Zhang, of email: Rufang Hospital Children’s author: email: China, Co-corresponding Shanghai, District, Putuo Hospital Road, Children’s Surgery, Luding Cardiac Central of of 18964647822 and 355 Department of of Shen No. researcher Director and Shanghai, Li Vice is Zhang of Ph.D, RuFang Ge, SHEN, masters. Lan Shen, LI Junwen are Li Xiaoping author: authors Li, of Corresponding other degree Jia Surgery. and academic Cardiac Qi, highest doctor, The are of Muyu Lan Shanghai. department of Xiaoping Shanghai. the Hospital of Children’s of of Hospital doctors Laboratory ZHANG Children’s are RUFANG from Zhang SHEN, are LI Rufang authors GE, JUNWEN these LI, All JIA LAN, Atresia Pulmonary XIAOPING in QI, Variant BMPR2 MUYU Pathogenic mutation. Novel harmful highly a a was Identifies mutation be Sequencing The to Exome it 246048). Whole predicts (1/ tolerant) population c.2804C from normal our intorlerant of the To frequency (sorting in Conclusion The SIFT low members. And atresia. extremely pulmonary family is species. for other family different responsible in this in variant conservative not in BMPR2 c.2804C detected but the in at mutation report brother(III-1), A935V) detected was to elder study was (p. proband’s first the inheritance pathogenic the of maternal is The DNA this from DNA. knowledge, genomic originated the genomic the Results using mutation in proband’s Panel. extracted detected heterozygous the gene was also sequencing A of DNA second-generation genomic gene the follows: the using BMPR2 as and performed the collected, indicates was an were detection results family by gene testing PA The characterized pulmonary a Genetic Kit. of in mainly approaches atresia Mini members therapeutic pulmonary Blood defect six and DNA a diagnosis, of QIAamp in prenatal samples future congenital mutation Blood counseling, gene cyanotic genetic Methods disease-causing the complex atresia. of a method defining of possible herefore, a type . becomes rare family pulmonary or a valve is pulmonary (PA) undeveloped atresia Pulmonary Objective Abstract 2020 13, November 1 hnhiCide’ Hospital Children’s Shanghai [email protected] 1 hns ainlNtrlSineFudto,N.8319.Tesosro hsfn salso is fund this of sponsor The 81371499. No. Foundation, Science Natural National Chinese ioigLan Xiaoping , umnr tei;gn uain MR gene BMPR2 mutation; gene atresia; pulmonary hl xm eunigIetfisavrati PA in variant a Identifies Sequencing Exome Whole 3118 1 uagZhang Rufang , e:18917128398 Tel: , 1 i Li Jia , 1 1 uwnGe Junwen , 1 n iShen Li and , > p 95) h uainwas mutation The A935V). (p. T [email protected] 1 ,Tel: > T Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. irvsua nohla el HVC) ua miia enedteilcls(UEs,adaortic and (HUVECs), cells endothelial umbilical human human cells with associated endothelial (HMVECs), be cells to reported endothelial is microvascular cascade asso- metabolic signaling obesity, particularly BMPR2-mediated are cancers, canonical (PAH), development, changes vascular the on these hypertension of and arterial so Variations gene, pulmonary and the development. including diseases of vascular disorders fuctions of clinical and domains step with construcions cytoplasmic every ciatied various to almost C-terminal leads enhances and gene BMPR2 kinase, BMPR2 or the transmembrane, development that the extracellular, presented in as function Reports such both receptors fields 1 bones various type and within corresponding organs its embryos, and and the vasculogenesis, BMPR2 of muscle, the differentiation smooth , vascular far So pulmonary endothelium, osteogenesis. vascular pulmonary including organs, factor- etc growth and transforming the MTHFR GDF1, GJA1, CHRNE, GJA5, CUBN,CAMTA2, includes B12 CNVs ARSB,DMGDH, vitamin these BCL9,etc and AP3B, in folate GJA8, PDE88, located , DHFR, ENO,GJA5 TBX1, related GP18A, NDE1, the 5q14.1, And ABCC6, 5q14.1, deletion. MYH11, 16p13.1, the deletion, including chro- 17q13.2 heterozygous PA, includes and of 1q21.1 mainly duplication pathogenesis variation chromosome 10p13 greatly the Chromosomal deletion, with will mutation. heterozygous associated gene 22q11.2 methods be single treatment.mosome biomarker to and and variation found or diagnosis number been genetic copy early have chromosome variants gain through PA genetic period several with present, children fetal At that even poor so or still rate, neonatal is detection PA the the of increase in prognosis and PA causes the radiation with it improved, intraoperative children complications reducing been the mostly have reduce while management assists procedure, technology perioperative printing partly surgical 3D the and with of load, children accuracy contrast of the modeling improve computer to personalized helps about years, 50% is recent as deletion in heterozygous technology high this printing as of incidence be the can Fallot, of deletion tetralogy with range PA the with and children 13% Mbs 22q11.2, In 2706 of chromosome to 40%. loss of Mbs to deletion the 1437 30% heterozygous from to the was the leads deletion to of the which related disappearance of development closely the ventricular is PA with right Presently combine poor clinically. repair is often a PA biventricular patients in the of Such resulting of opportunities PA pulmonary integrity tract, syndrome. the and septal outflow dysplasia (PA/VSD) patent ventricular Accordingly, ventricular heart the defect right defect, right them, survive. septal as septum Among ventricular cannot (PA/IVS). known from ventricular with patients oxygen septum also atresia as ventricular up the pulmonary intact pick such Otherwise with to categories: , atresia two blood These defect. their into the septum survive. for divided or to atrial possible is heart diseases it and among heart make arteriosus other that passages ductus shunts with natural right combine those to some could left especially patients through it PA children, make the other diseases potential Usually or heart PA. all from multiple detect suffer including arteries(MAPCAs) pulmonary not care purely collateral of medical could artery-pulmonary progression of examination major of lifetime with ultrasound prognosis of understanding choice However, better poor the morbidity old a with for interventions. The years and points malformations 2 crucial technology lungs. within heart become ultrasound the die atresia, congenital prenatal from defect all oxygen of septal ventricular development up pulmonary of with pick a or -3.4% atresia to valve pulmonary 1.3% heart pulmonary with is the children undeveloped from disease an travel the complex by blood of of type the characterized rare obstructing a mainly is thus defect atresia artery, Pulmonary heart malformation. birth congenital common cyanotic most the is disease heart Congenital Introduction: 6 I h hl a ao reyploayclaea reis(ACs,teicdneo heterozygous of incidence the (MAPCAs), arteries collateral artery-pulmonary major has child the .If 20 . 15-19 MR ly motn oe nvrosbooia ahas n opooethe promote to and pathways, biological various in roles important plays BMPR2 . 12,13 ttesm ie eea igegn uainstswr lofud including found, also were sites mutation gene single several time, same the At . 7 β A rsn,temi ramn fP ssilsrey ihters f3D of rise the With surgery. still is PA of treatment main the present, .At uefml eetr,wihprom ies oe nvrostsusand tissues various in roles diverse performs which receptors, superfamily 4 hrfr hlrnwt Aotndvlphatfiueadcyanosis and failure heart develop often PA with children Therefore . 1 5,11 oemrhgntcpoentp eetr(MR)i n of one is (BMPR2) receptor 2 type morphogenetic Bone . hs ee eerpre ob eae otemtbls in metabolism the to related be to reported were genes These . 5 14 h ai fdlto uainaogteptet sabout is patients the among mutation deletion of ratio The . h MR ossso ,3 mn cd,adfunctions and acids, amino 1,038 of consists BMPR2 The . 2 3 ne omlcrusacs ainsd not do patients circumstances, normal Under . 8,9 lhuhtesria ehiu and technique surgical the Although . 10 Teeoe cenn for screening .Therefore, 2 uigteftllife, fetal the During . 1 bu 0 of 20% About . 15 . Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. mgn pcait norhsia.Tepyia xmnto hwdcaoi,wezn,adsotesof shortness and wheezing, , showed two examination as physical well The as surgeons hospital. cardiothoracic two our by in performed specialists were of imaging assessment degree imaging the and and examination evaluation Physical valve, imaging tricuspid and the assessed examination of are Physical size children 1.2.2 the Postpartum , detected. right the be of also function can and ultrasound reflux size abnormal such Doppler addition, the of color In measuring arteries second four-dimensional ventricle. by right various the fetal and the in valve Such tricuspid early between artery, color method. pulmonary diagnosed reflux four-dimensional the this be in with with exist could weeks) diagnosed mainly PA abnormalities (18-22 And mainly pregnancy was performance. 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Anhui Children’s from Shanghai family Surgery, PA Cardiothoracic the collected cases study PA This the of features clinical 1.1 methods and to study Data first 1 the is PA. this heritable knowledge, for our variant To disease-causing development. a heart as c.2804C With uncover the BMPR2 To at members. in the family variant members. function report six novel unaffected may on four which a sequencing variant, and exome identified causing affected whole we two performed with we tools, variants, family bioinformatics or PA genes a pathogenic collected novel we the study, present the In iue1 Figure 21,22 . .Tepoadsedrbohrwsdansda umnr tei ihvnrclrseptum ventricular with atresia pulmonary as diagnosed was brother elder proband’s The ). 3 > p 95)i MR stedisease- the as BMPR2 in A935V) (p. T Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. n hnsbetdt usqetbonomtc nlss h agtae oeaews9.1,average 99.41%, was filtered coverage finely area were target sample The each analysis. chromosomal of any subjected bioinformatics sequencing show were subsequent by not normal family to did obtained a the PA subjected revealed sequences with in members then sequencing proband PA family and the original without these on The members on performed karyotype family array-CGH imbalance. standard the other Firstly, Then and karyotype. analysis. patients 46,XY PA sequencing of exome full cases to 2 study, DGV this In analysis: Cytoge- the with Results for 2 analysed av- used and 13kb were scanner a databases with Agilent following probes the www.ncbi.nlm.nih.gov) (https:// 000 The with and PubMed (https://www.orpha.net/consor/cgi-bin/index.php) 180 Orphanet scanned Clin- 1.3.1, (https://www.clinicalgenome.org/), contain (https://www.omim.org), were Gen OMIM (Agilent). microarrays step (https://decipher.sanger.ac.uk/), Arrays DECIPHER software These (http://dgv.tcag.ca), in CA). 3.0.2.11 spacing. 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Data may be preliminary. soitdwt h ahgnsso otdsae,icuigfmla umnr yetnin(A)and (PAH) are hypertension 2q33 chromosome pulmonary on familial located including gene (112262) diseases, BMPR2 BMP4 most the and in of mutations BMP7, pathogenesis that cells, the found COS-1 with have transfected studies associated Most that discovered BMPR1. first of PA BMPR2 etc. al in to MTHFR, et result linked and GDF1, Rosenzweig were also 5q14.1, GJA1, 5q14.1, may 1995, 16p13.1, chromosome GJA5, In as 17q13.2 PA. that such the found affects of years, of CAMT2 deletion recent repetition regulates the the Similarly, deletion and mutation. 17q13.2 10p13 gene and GJA5 the B12, by vitamin disease and heart 2014, acid congenital In MTHFR folic metabolism, folate-mediated studies. of NKX2.5 regulate more metabolism CUBN10p13 and the and more DHFR5q14.1 regulates PA by of and mutations variation confirmed number repeated been copy which between 17p13.2 has relationship PA and the of discovered 16p13.1,22q11.2,5q14.1,10p1 first pathogenesis al genetic BMPR2 et the Xie and enzymes kD) years, related 50-55 recent and (about In superfamily BMPR1 TGF receptors: surface The cell heteropolypeptide kD). the role. of 70-80 to regulatory types (about binds two a BMP2 through play When signals can superfamily. transmit development it TGF-beta and receptor, the growth embryonic kinase in so affect cytokine threonine/serine and can multifunctional MYH10) that the and cells to LRP1, nerve DAW1, belongs and (DGCR2, HAND1, chondrocytes, CHD TSC2, as osteoblasts, MYH6, inheri- such as and classic level, recessive such NSD1, animal the the NOTCH1, at to control FBN2, remain genes addition COL5A2, only on that These COL1A1, in genes CHD7, years, discovered. as including recent well been disease as have In heart genes congenital 1.3%-3.4%. study, new of is present some tance PA the etc., gene. family, of disease-causing In malformations congenital HEY the incidence in factors. identify HAND2, the disease to genetic heart and family congenital to PA of 28%, related the incidence is of the mainly that members complex, is shown six have is PA on studies disease that Epidemiological PA sequencing shown of exome etiology have whole The performed studies we disease. more heart and congenital more cyanotic complex and common is disease PA The The controls. of normal mutation Discussion as no treated And were the family and found. this PA was in of gene members mutated cases family two the other in of the presented of carrier of was samples a samples mutation blood be blood the to the in considered in BMPR2 was BMPR2 who of mother Mutation c.2804C proband’s gene with (1/246048). BMPR2 disease. the gnomAD associated the in database with be mutation accosiated heterozygous to was A proved PA. mutation that of were the demonstrate opinion, results gene sequencing our the exome in Whole c.2804C of so variant PAH, construcions missense as homozygous of such novel this changes diseases a carries in the pulmonary identified who found test BMPR2.Moreover, mother was Our mutation the the in one and disease. to A935V) disease, only this according Furthermore, the with 22.8. gained symptoms. associated was children family diseases uncertain two CADD cardiovascular variant the of was develop SIFT mutation both mutation score our by family, the the The refine harmful al., this to does functionally et database. in Richards order control any be (VUS).But by In in significance to normal interpretations(ACMG) variant predicted reported a mutation. genetic were not as shared gene for that were gene candidate guidelines considered mutations which mutated a is for and the as screened who CADD, of considered finally sister and carrier was we proband’s a mutations, gene the be mutant of that to list the variation considered Therefore, was the have. who And not mother proband’s gene. the mutant and the PA of cases Two depth coverage 1 oemrhgntcpoen(M)i ru fpoen htpooebn omto n c ncells on act and formation bone promote that of group a is (BMP) protein morphogenetic Bone . 24 I 02 omd ta rtpooe htte12. uaini osbeptoeei of pathogenesis possible a is mutation 1q21.1 the that proposed first al et Soemedi 2012, .In > 0.Tewoeeoecpuewsscesu n h eunigqaiywsreliable. was quality sequencing the and successful was capture exome whole The 20x. 27 11 Adteceia od ewe hs oncin r nysal ntepresence the in stable only are connections these between bonds chemical the .And twsfudb oynme aito nlssta oto h Awscaused was PA the of most that analysis variation number copy by found was It . iue3 Figure . 5 hr r orrr ahgncmttoslaigt A in PA, to leading mutations pathogenic rare four are There . BMPR2 5 eemtto a erltdt h pathogenesis the to related be may mutation gene > p 95)wsrrl on ntenormal the in found rarely was A935V) (p. T 7,26 a erltdt h ahgnssof pathogenesis the to related be may . 25 Snl eelcsrsac,in research, locus gene .Single 5 hs aitosinclude variations These . 23 > .BMP (p. T Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. i aiymmespoie rte nomdcnetfrtepbiaino h rbn’ identifiable proband’s the of the publication of and the committee proband in ethics for The members the consent participants. family by informed all his approved written from was and obtained provided information. project proband was members consent The the family informed of his and Helsinki. analysis Hospital of Children’s genomic Declaration Shanghai for the consent with informed accordance written obtained We Statement of Ethics the importance heterogeneity. in phenotypic sequencing the exome possible highlights whole with by case diseases present analysis heart Our This genetic PA. congenital quality with rare high diagnosed of family. of the screening clinically diagnosis of Chinese genetic patients significance molecular molecular the a the Hence, confirm emphasizes in possibly gene. also PA BMPR2 to study in considered rare mutation be with of could associated BMPR2gene case PA the clinical of diagnosis a clinical report we Here, signaling important the Remarks in of breakthroughs Concluding one the be of may one be family may PA BMP pathway and the signaling cases BMP that PA. prevalence PA. of sporadic genotype-phenotype. lead suggests overall of between pathogenesis PA does also pathogenesis the the association mutation of the study the the verify number in elucidate this whether involved to large and determine time, molecules pathogenesis, necessary a to same its needed in also the and are population PA is At experiments of PA vitro it pathogenesis the related in However, the closely and in to vivo be gene family. in may BMPR2 Further possibly this the gene is the families. this pathway But in recognized signaling in in PA. PA also BMP mutations mutations of that of is that of pathogenesis family PA pathogenesis confirmed PA the of a and the in with development pathogenesis found to cardiac associated the study the are This in with mutations unclear. role associated still Gene diseases important is PA an clear, common researchers. of relatively play for and pathogenesis are factors PA clinicians used of genetic most options be can that by treatment can and concept only diseases. criteria also the not these diagnostic but and of manifestations, which capture pathogenesis clinical diseases, genome, sequence the genetic summary, genetic the the target In revealing rare of uses Thereby regions of sequencing genes. exome genes multiple exome by all pathogenic Whole caused from the DNA a detect samples. technology in high-throughput quickly patient sequencing members capture second-generation of family high-throughput to mutation sequencing performed technology candidate exome we but and study, stage, whole sequencing unclear experiment this exome animal for still In the full is member. in PA performing or family by of stage, PA PA pathogenesis screening of the or pathogenesis screening and the the carrys them in between who either correlation disease is mother cardiovascular genes the proband’s other these and of the obesity study obesity and as The including well disease, symptoms as typical the PAH presents develop as also brother such gene symptoms. diseases the proband’s cardiovascular other of the typical And prominently mutation pathway. and BMPR2 to basis the signaling that genetic lead proband WNT shown the also the canonical is been could with family Both has mutations mutation This associated It new the PA. is family. PA, unreported of and this profile development than the in vascular PA genetic that the of the found pathogenesis in increasing was PA, the expressed It of to in pathogenesis related generations. sequencing the be Sanger three may of and gene from analysis BMPR2 inherited bioinformatics the families sequencing, in PA exome of NIPA1 complete of family a action a performed the we study, by this caused In syndrome Prader-Willi the BMPR2: with experiments interact animal in atherosclerosis (PVOD) trigger disease veno-occlusive pulmonary 28 29 eti eein fteBP2gn aebe hw to shown been have gene BMPR2 the of deletions Certain . loicue r oeo h iesscue ygnsthat genes by caused diseases the of some are included Also . 6 210029 32313030 30 hssuyi overify to is study This . . 31 . Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. tei ihitc etiua etm otnsriosrmi trs flt ycrilicamaand pulmonary ischaemia for myocardial palliation late single-ventricle of of risk outcomes atresia. at Long-term pulmonary remain al. for survivors et Fontan genetics K, septum: molecular Plessis ventricular death. du in intact CL, with Advances Poh atresia P, J. Elias Zheng 2. X, He M, 2017;27(2):207-216. Gao 1. References species. elder various proband’s in the proband’s conserved the and mother, highly grandmother proband’s is proband’s the mutation proband, the the The grandfather, for B: proband’s represents 6 the brother. Line sister, to proband’s 1 Line the increased father, an 6). and presents 75.9%. 1,2 which (Line surgery, about brother was before der proband proband the the of 3(A-B) of ST chest FIGURE ratio in the cardiothoracic change of the hypertrophy, X-ray ventricular And the hypertrophy, the is shadow. 2C.D atrial of electrocardiogram 2F heart ; the an artery Figure is descending presents pulmonary waves. 2E the which Figure T narrow was surgery, valve). and artery a before pulmonary pulmonary shows undeveloped proband the an arrow the of as red well of supply as the blood atresia (2A. the pulmonary show shows surgery both arrow before red scan the 2B. CT proband; the are 2A-2D Figure longer chest. of no X-ray is and arrow) (A-F): (red 2 white proband and FIGURE The Black respectively. females. represent individuals, circles unaffected (III-2”). and alive and males, affected indicate Squares represent symbols individuals. affected two them. with to family known not family. or PA 1 present this FIGURE not in prsents, presented family this symptoms of the member presents 1 1:Table TABLE tables and Figures interests competing no have they that declare authors The Statement for Interest accountable be of to Conflict agreement MQ, and workup. published patient be JG: to and version ,JL the RZ work. for LS, approval the ; final of analysis JG: aspects genetic and all XL: JL manuscript; RZ, the LS, perfect XL, and drafting : MQ Statement Contributions supported was Author work This participation. their for members family his Hospital. and Children’s patient Shanghai the by to thanks sincere Our Acknowledgements u adohrcSurg. Cardiothorac J Eur h eireo he eeain fteP aiyPdge ftetregnrto,Chinese three-generation, the of family.Pedigree PA the of generations three of pedigree The : :Amtto a on ntepoad rbn’ ohra ela h rbn’ el- proband’s the as well as mother proband’s proband, the in found was mutation A A: : h eeataxlayeaiain eoetesrey Tsa,electrocardiogram scan, CT surgery: the before examinations auxiliary relevant The 2018;53(6):1230-1236. 7 ,adN rsnsthe presents NA and /, , ado Young. Cardiol Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 orsT aaiiD hap ,e l umnr tnssadarsawt natvnrclrseptum ventricular intact with atresia and stenosis vein Pulmonary umbilical al. human et on E, life. 2 Chiappa prenatal D, protein during Paladini morphogenetic T, bone Todros of 21. Effects Trial GB. Stark randomized S, prospective, cells. open Hager endothelial versus multicenter, G, gastrectomy III Finkenzeller laparoscopic phase of 20. mortality report–a and interim Morbidity an al. Trial). et cancer: (KLASS in GS, gastric signalling Cho protein for WJ, morphogenetic gastrectomy Hyung Bone HH, GR. Kim Brink 19. of den van review GJ, systematic Offerhaus A cancer. LL, V. colorectal Kodach Trevino JC, J, Hardwick Garcia-Pelaez 18. hypertension. D, arterial Rodriguez pulmonary pulmonary in C, in target mutations Jerjes-Sanchez therapeutic genetic G, a Garcia-Rivas as receptor II 17. morpho- type bone BMP P. in Dijke defects Ten hypertension. functional MC, arterial to Gomez-Puerto linked M, significance Orriols Clinical 16. BMPR2. al. receptor, et 2 HR, type Chang in protein SY, receptors genetic expression. Park protein gallbladder trkC morphogenetic M-J, human regulating bone Kim in of the 15. Development roles in JA. possible Kessler cubilin and QB, system and Song nervous Megalin MF, the Mehler DM, al. Zhang et 14. M, Lambropoulou E, Chatzaki epithelium. AK, Tsaroucha 13. overview. an controls. receptor: 6760 epithelial multifunctional rearrangements and a Jmm. 1q21.1 Cubilin, patients chromosome R. disease Kozyraki of effect heart 12. Phenotype-specific congenital al. 2436 et in IJ, atresia 2012;21(7):1513-1520. duplications pulmonary Wilson of GJA5 A, diagnosis Topf delayed and the R, for Soemedi outcomes and strategy 11. Surgical congenital in al. septum. et treatment ventricular G, planning intact Shi for B, with Gao simulations X, Patient-specific He al. 10. et G, Giusti E, disease. Sauvage heart C, the Capelli with polymorphisms population. 9. GAP gene Han 1 alters Chinese factor 40 growth/differentiation the of in Association of disease 1299. al. carboxyl-terminus heart et congenital the T, You of in Y, risk variant Meng A X, Fallot. Sun al. of 8. tetralogy et for M, Perioper- risk Rocchetti and Collateral increases R, congenital and Status Aortopulmonary Ferese junctions with Deletion Multiple V, patients 22q11.2 and Guida in Atresia E. 7. variants Goldmuntz Pulmonary number RE, with Tanel Fallot copy NM, novo of Tetralogy Pinto Vessels. de for OU, Rare Outcomes Elci ative L, al. Mercer-Rosa et WZ, 6. Zhang JL, Chen atresia. 2018:373-377.e371. L, pulmonary Atresia. Xie and Stenosis defect. 5. Pulmonary septal ventricular JM. with Martinez atresia O, pulmonary Gomez of diagnosis 4. Prenatal al. (2001). et Ultrason XX, Med Tian J PH, Luo SH, Yang 3. 2001;79(4):161-167. eit Cardiol. Pediatr lncladEprmna . Experimental and Clinical nefc Focus. Interface naso surgery. of Annals irvsua Research. Microvascular auervesCancer. reviews Nature LSOne. PLoS lrsudi bttis&Gynecology. & in Ultrasound ellradmlclrlf cecs:CMLS. : sciences life molecular and Cellular 2018;45(2):341-344. 2018. 2014;9(5):e96471. Cardiol. J 2018;8(1):20170021. 2010;251(3):417-420. M Reports. BMB 2018. 2008;8(10):806-812. 2012;84(1):81-85. 2008;8(3):165-170. u u Genet. Hum J Eur 8 M e Genet. Med BMC 2017;50(6):308-317. 2003;21(3):228-233. oeua ilg Reports. Biology Molecular 2017;74(16):2979-2995. Neurosci. J 2013;21(1):69-75. 2017;18(1):82. ora fMlclrMedicine- Molecular of Journal 1998;18(9):3314-3326. u o Genet. Mol Hum 2013;40(2):1291- Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. sequencing-identifies-a-novel-pathogenic-bmpr2-variant-in-pulmonary-atresia energy probands. disease and 1.pdf heart adipogenesis congenital TABLE 2,871 in in variants proteins novo file morphogenetic de Hosted and bone inherited rare of of role Contribution 32. Emerging YH. Tseng TJ, and metabolism. spastin Schulz NIPA1, proteins paraplegia signalling. spastic 31. hereditary BMP The mammalian of al. et inhibitors X, are Wang TL, spartin Edwards HTH, Tsang 30. clinic. the in Atherosclerosis. hypertension A. pulmonary 491. Daugherty of H, Genetics Lu M. 29. Humbert D, medicine. Montani pulmonary E, in receptor Lau II opinion type B, human Girerd a of characterization 28. heart and Cloning Congenital proteins. al. EH. morphogenetic et T, Zackai bone Okadome for T, DM, Imamura BL, McDonald-McGinn Rosenzweig in cases. HA, 27. analysis two Feret of spectra A, Report number Wilkens copy dysplasia: AM, A. gene oculodentodigital Lippa Human in K, defects al. Izumi et CA, 26. Struble DK, malformations. Mahnke heart growth congenital A, cardiac Tomita-Mitchell stimulates CAMTA2 coactivator transcriptional 25. deacetylases. The histone al. II et class kinase J, proteins-2-inducible McAnally opposing morphogenetic J, by Backs bone hip. K, in the Song mutation of recurrent 24. dysplasia A developmental al. with et associated S, Wang is Z, gene Zhou L, Zhao obstruc- 23. tract connections. outflow ventriculocoronary ventricular of right of detection diagnosis and Prenatal septum, 668. al. ventricular et intact LK, with Hornberger tion C, Boutin YV, Maeno 22. 2013;161(12):3150-3154. yoie&Got atrReviews. Factor Growth & Cytokine vial at available hsooia Genomics. Physiological https://authorea.com/users/375564/articles/492750-whole-exome- 2017;23(5):386-391. rceig fteNtoa cdm fSciences. of Academy National the of Proceedings reislrss hobss n aclrbiology. vascular and thrombosis, Arteriosclerosis, Cell. 2006;125(3):453-466. 2009;20(5-6):523-531. 9 ua oeua Genetics. Molecular Human 2012;44(9):518-541. x hrMed. Ther Exp mrcnJunlo eia eeisPart Genetics Medical of Journal American 2017;13(5):1773-1778. 2009;18(20):3805-3821. 1995;92:7632-7636. Heart. 2015;35(3):485- 1999;81(6):661- Current Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 10 Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 11 Posted on Authorea 13 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160526348.88194656/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 12