fey genes (ibe) Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics “Thomas Eggermans® Insta of Human Geet, Univer Hosp RUTH Aachen, aust 30,74 Aan, Geman ‘semaneuancen dee: 19-4506 Fe 8.2408 Recied M November 2 Acs 1 Dect 0 Publ 5 Decor 220 Abstract Prenatal detection of unparental disomy {UPD)isa methodological challenge, anda postive testing el equi comprehensive considerations on he clinical consequences swell a ethial ‘Bees Whereas pret tting for UPD in fais which ae prone o UPD formation (cae ‘hromosomal variants, imprinting ssc ise embedded in netic nein he incidental ‘entation of UPD ten move dial to manage. With the nceasing application of high esltion ‘epson enabling the Merion of UPD, anincresce in pregnancies with ncenal detection of UPD an be expected. This paper willeover dhe current knowledge. uniparental dsomies their linia consequences with foes on prenatal tasting, gunti specs and poedapeitions, genic ‘ouncling, a wll a methods conventional fests high-throughput asa) Keywords unponnt dsomy prenatal ting ext generation nomi non-invasive prenatal Sing 1. Anroduction (Chromosomal abnormalities significantly contrite to repetitive failure al congenial disorders in humans, ane mots errors resting in aneuploidy acount for the majority of fst trimester pregnancy lnses, Are of meiotic or mii chremosomal mlsepregation = unparentat sisomy {UPD Figure, the exceptional inheiance ofthe to chromnones of prom the sme patent] hich in contrast to numeri or tract chromosomal aberration, does not alt number bel stuctre of chromonomen. UPD therlore scapes cytogenetic detection, but with he incest {pplication of high resltion an hraphputanalsiein diagnos genetic esting iis tet UPD has meanveile ben eported for neatly all aman chromosomes. In prenatal dlagnoss it ‘canbe detected asa incidental nding in the course of genetic ests based on unircied approaches lke genome-wide says These ests compese micrar-tased molecule kayoWping methods and next generation sequencing (NGS) approaches an! they are increasing implement in pret [Reetic testing. Inf, n case of UPD detection, the decison onthe farther management of the ‘Pregnancy requis considerations on methodological aspects inal onl ethical ese. oe B12, 184 dL DM poNE UL ropesFig Sch depicting te our jr faion mae of lke heen paren ‘Shonics(LPDn, Asean be dinate Hom thw made omaton, ores UPD cl ine tswellmananepliy line spencer ecu and pty eos (arte ‘eis se, shoul be not atin he of meson rece ar poset onluncton, tera, panel rin an be nk seth wpe se Fem sfacgantl UPD ar wll ss UPDe cus by arutral coma arantsie Ratermonn tera at shawn eth oe ee 2, ‘Two types of UPD can be discriminated: sm uniparetaheterodsomy (UPAD), the ell has inherits the two dierent chromosomes om the same parent, whereas in unparental odo {(LIRD) the sme chromonome hasbeen transite vce Figure Infact complete UPAD or UPD afecting.a whole chromesome can be observed, bt feguently stiches of UPAD alternate with UND regions o the afc chromosome (ned UPRDUPD) ‘Armjorexcepton pteral UPD 11 Beckwith Wiedemann syndrome (BS) (Table) which is ‘excusiely UPD. UPD doesnot alvaysatict a whole chrumosome but als segmental UPD (ao eld Partial UPD) comprising oly segments fx chromosome have ee reports or eve 1 ‘UPD can accur after meiotic onsjuntional eros, bu mitotic formation mechanisms have ‘ben ened a wel Figure (@) The mujor formation mechanism i risomic rescue, withthe subsequent low of one of the supernumerary chromosomes as a prerequisite forthe cell to survive In oe thi ofthese reductions, the chremesome fom the parent cantabuting ony ane chromosome othe same rescues ost thus giving rie to a UPD. (©) Gamete complementation denies he fetzation ofa dnomic gamete anlivomic gamete nds therefore also theres of meiotic errors. The esl complete UPAD. (6) Survival ofa monosamic gamete is possible by monosomic rescue vin endoduplication, resting Incomplete UPD. (8) Postetization UPD formation consists of mitotic malsegzegtons either causing a moncsomic cll with subsequent endodupliction, fan endeduplication followed by a chtemosomal las In any cee, posaygotic UPD a complete UND. Depending en theme of meiotic oe mitt nensuncton UPDS can cur aka mesic ontaton, ‘venincombinten vith somic cells (Figure), Acovdingly detection of UPDscanbesigniicanly Tampere by the c-cecurrence of chromosomal mesaesm, and UPDs might therlorescape detection,“able. Unipat hosen (UPD for which an meciston with cngeitaldsrers own dc rte ating am a BOkmemaan, peony Cpe cin too cto GR gianni EMIS tame Co oo iam Ne aT ee 7 uch ens = mons sae sca a lester —— ed upanpispa “Sedna vas 2 aay, Goes Ye et ‘mente temas ce occa Shorea IR mere veatssmn SME rsaymne——Sgom eh ‘ge tone TERESA wu a testes stro ox epieieHISSS nu opatimeatner Ne ne irene “tony pega BOBS ke » wc ‘eric Ne DM ty oetasuape nwimmgemow ts) ame om keene ns : mer Parte s oaligpaie ersosmame Om 22380, men sox soci’ te Tiree Upton? Indic slow alan ‘wor Cela A omy eI entirety ‘See epee, paar ee Uae an iter meme wo uptime Salama om wee Tokeingeiate MC LL ET RRR TT AT NT PS RET43. Risk Factors Predispsing for UPD Fonation By tisomic rescue every human chromosome san be affect by UPD, ant UPD has meanshile ‘been porte for neatly al human chromosomes (or review: Lice T2020 Cases with unipaental soy ipl de/D8/CA/UPDAStare hn aces 11 May 202). Accordingly the frequency ‘of single UPDs coeelates with hat ofthe respective somes in mans. In act tsomy 161s the most common autosomal trisomy in humans [2] and nearly ll isomy 16 pregnancies originate from maternal mei eros [2°] stherefor not surprising tht mate UPD of cromorome 1 ‘pat toimat occurs relatively frequently for review: The link between trisomy an UPD is alsa refs by incensed maternal agen UPRD in “comparison to UND (eg. for upd(7iat 25) an increased materal ages a relevant ink actor fo tesa frmation, ant s0 i for UPD formation Up to 6% of UPD ate detect in inva witha normal karyotype (46, XX: 6, XY) [2 and the oters ae associated with eomesomal reatangemens. As these variants predispose fan improper chromosomal segreotion in meiosis and mitosis, they can be regaled os another Fk actor fo UPD formation. In principle nearly every type of rerangement can cause 3 UPD (lor eview:[27), btn particular is famies ransmiting Robertsonian tennocaions (ROBT) ae trek for UPD formation. Robe rest from shoe am reerangements of the five accent ‘uomosomes (chromosomes 13,14, 15,21, 22)and have a ineldence af in 1.00 inthe general population for review: [25 Due o this frequency and he nereased sk of RTH caries for trisomy land sleet UPD formation, n parila, UPDs of he cinially relevant chromosomes Hand ave constantly identified in routine genetic testing. Another group of strctral variants prone {to UPD formation ae small supernumerary isochromosomes but these ae not restricted to specie domosomes P5). 4. Clnial Consequences of UPD. Up to now, eo waysto impact the phenotype have been reportet for UPD Le, by disturbing Inmprinted chromosomal regions an By eduction in reves lees to homczygoity (igure 2) ‘Asa third way, the posible association with aneuploid ell ines with impact on the phenotypes ‘worthy of meson Ee es torte “oy Sas —— re cael eee) | a igate2. Oversea he inden for npn ny (UPD) esting he anton cares nals eutcemes of UPD, (IPT—norinvatve protein LOH Hos hetero, (Cvs chvone illo sping)‘The most prominent clinal outcome of UPDs ave imprinting dsowders Table 1. Ipeating isders an caused by aeration othe balanced moncllcandparent--orign specific expression ‘of imprint genes [1 an UPD ong the spectrum of molecular disrbances inthis soup ‘of congeritalisorders. Though more than 109 human gees ate regulted by genomic imprinting, they tend to cluster and therfore UPD of ony some chromesomes and chromosomal regions ate ‘associated with imprinting dlsorder phenotypes. lina, imprinting disorders ae heterogeneous, bul they share several features affecting growth, metabolism and poychomotoric development I prental contest, grove diaturnces abominal wall delecs an polaris might be incatve for dete imprining but are of cours nspesite. Though the contribution of UPD the molecule spectrum of imprinting disorder vary betwee the ifrentchromonomes it shot ‘be noted that UPDs were the first molecule alterations which have ben described for some of the disorder (eg Ser Russell yndome, Temple syndrome, Kagam-Ogatasyurame (KOSI), Mulehanni-Bioy-Conlin syne). ‘As not all human chromosomes harbor imprinted regons, UPDs of single chromesomes can remain without clinal consequence. However, the risk of UPID in general is in the weducion in heterorygosty for receive pathogenic warans to homozygosity and the fist case of molecularly proven UPD was a patent with up) sullen fom cystic boss da to homozygosity of ‘pO inthe CFTR gee [3] Inthe meantime, considerable numberof patents with unexpected homozygosity dueto UPIDhas ben reported. Ths identifcation of UD fra chromosomal segment Inassocation with inal features mht lp to deni the molecular cause ofthe dsease based on homasygority fora erie pathogen variant (eg 12, "As UPD can be associ with trisomy mesic dc ois mode of formation; lnc feaues might also be caused andor modifi bythe presence of isomiccel line. In principle this possiblity {pple oral UPDs, but depending onthe formation mechanism andthe gene content of he fetes ‘gion, trisomy mosaicism doesnot play a elevan rol. However, in some imprinting disorders ‘mosaic forthe UPD is coreated with he severity ofthe disease (eg, upu(l)pat a BWS) Inthe ‘lows printing disor, som mossicnm canbe nefected to have acini imp hee {rea est hoo chromosomal conetuttons fr which the pathogenetic infiene of ithe he trisomy ‘mosacbm ov the UPD isclscussed: fr up(6}nat the lial heterogenety hasbeen atebuted to ‘mosaic sony 16 cll lines [17 but the reentdenticaio of case wih i olated methyation left [5 sda ha atleast some features night be Linke an eprint defect. Incase of "update impact of risomy 6 cel ines hos been suxgets 5] whereas further even fr an Imprinting eet has ot yet been published 5. Techniques to Detect UPDS Techniques 1 detect UPDs are generally based on genetic poly momphises, and the segregation analysis of polymorphic alles nthe patent and her parents. Ths, the fal prof of UPD canon ‘be obtained bythe comparative analysis ofthe genotype ofthe patient with thos of thelr parent In assical UPD testing, short tandem repeat (STR, microsatellite) analysis the most often used tool as teas be conducted easily ata low pice STRS are DNA stretches containing repeat unis of ‘benween two ar seven mets nent that are tandemly repeated. Therefore ths clas of markers has high information value. With the exception of single STR associated with wieletide repeat disorder, their gts tram! tesco generation to generation, and can thenetore ‘beused to trace the tranenittance of alleles and chromosomal gions Figure), UPD can alo be ‘enti by other marker oyster ike single nucleotide polymorph (SNF) but these analyses ‘ie the analyses of larger numberof markers SNPs commonly only consi of fwoalleles and the information content of single SNP is much ower that ofan STR.» - Lh i doa he eee al ah » * om) © Set manne | — gute Stancanl moleclar mete ii pret sony (UPD) a} Sheet ade pea (STR) eng iltting anor trina (UPD) aps: DISSI23) epretal Isso UPD) (up D181) ar wa up tna BS pet arr DISS Inher wher he nh pel lke ows aah rene ns), De ‘sgnentl URDet eemoname by sing ule plymorphim GNP) aay ana Cyan, ‘Nar Ahmet, Sint Clr CA USA?) thr fmt tee LOH purple am, cocrspondng UPD) nerd by non-LOH sets probly representing UPAD; Bale ‘rogue deogram of chnome as! pil Beppo.) einen o he ‘pala by met atone mules lgtondependent prbe amplicon (MS MLPA), (apps panl copy number aaa, lower pana: mtyton aaa. The pt ahi norma copy umber in 1pISS, Hereby extn los or dupaton oh ease fr the ‘eran meta atthe imprinting mers Land 2, C2} Maton ale bows ypemetyltnof the patrol ety aed Can hypometylanf emaeryetyated Chenoa pitt canbe eit selon NSLP wing the MEIN-C3 sy nd ata anole bythe CaayerNet anwar, MRC Holand Astras NL USA However this problem icine by assays which allow the alysis of huge numberof rmarkersin parallel Examples areSNP arrays (Le, ed for molecular karyetyping) (Figure b) and INGStise eps. thal the dotcom of stetches floes of heterozygosity (LOH, te, techs ‘of homozygosity which might be caused by UPD. In alton, comparative analyses of the parental [genotypes and application of speci bninormatcs ole alos the detection of UPAD ae wel [3,5 Infact this comparison enables the final prof of UPD inthe majority of cases, but in famies witha high degree of consanguinity LOH might not be distinguishable from UPD.1m families suspicious for UPD affecting imprinted le this problem can be rcumvented by the use of methylationsspeiie (MS) tests in some situations. An example s parallel testing ofthe v0 “oppesitely imprint cin 1hp15.3 in Beckvith- Wiedemann syndrome: gain of methvaton a he tslomerc imprinting contol on (C1) an os of methatin ofthe centromeric region 12} nthe sae patient comsims the molecular diagno ofa pateral upp) Fig 7) summary, the commonly sed tests for UPD detection canbe dsciminat in those use for targeted detection of UPD STR typing MS tests), and those providing information ot UPD ab at ‘nein Hing (SNP ary, NGS). {6 UPD sand Prenatal Testing {na prenatal context, UPD iets the in the course of decd testing workup for UPD, ‘orincientlly (Figure). “eit group commonly comprises regnancisin amish known chmmosomalaberrtion predisposing for UPD formation, eg, RbTks. Though UPD formation cin ccc inthe coun of rondjunction of any chromosomal aration iis very rare andthe isk Figures ae heterogeneous Tne the major group at sk or ormatin ofa clinically relevant UPD are Reb earners fet ‘homssoaes tan 15. Fo thee structural arans, rk igure have bes determined shosnng that ‘air of inherit swell yde-nove Robs can eahibi UPD [fn ReBTK taney the sk for {UPD formation ina fetus th non-homologous RobThas been stmt 9s 16-08% [5] In rare cases, UPD testing might be nce in familes with imprinting dsonders due to _luomosomal rearrangement afletig the inated regions on the aforementioned chromesomes (able) In these cases, the type and consequence of aleration (nasi disturbance ofthe impested region by breakage, deletion or duplication) and the sex of the parent transiting the alteration has tobe considered. In particular, case ofthe imprinted chramosomal regions known to be ssscited with paren-of origin dependent phenolypes(PWS-AS,BWSSRS,TS11-KOSH)cliferent ‘nal outcomes canbe obuctved ithe alec chsomovome is ier either fons he mbes rn the father eg [). Tacidena identification of UPD can occur in the cours of ilferent prenatal stings, and the implementation of high-essution assays have boosted this observation. The ou of incidental diagnoses of LPDs cn be subside in two modes of asceraient (2) dentcaio via prenatal ‘eteton of [numeri oma aberrations and () by unexpected omy gy an sets ‘As described before (Figure 1), the major formation mechanism of UPD is trisomy rescue, and therefore UPD detection fe trisomy rescue isa wel-known phenomence in asia invasive prenatal ey togeneic analyses ln the past the som was typlly dente in codon ills ‘Sampling (CVS), bat due the lth of many tsomies, some rescue the only chance of the fetus to survive, ant therefore the tesomy sno tstabein etal isis fe, amniotic cls) (conned placenta mosaicism (CPM) However in the cours ofthis resce, UPD might occur. case ‘ef chvomesomes which do not habor imprinted genes or recessive pathogenic alleles, Use UPDs ‘emaia undetected, bu they are denied incase cally eelevan sequences are acid. Therefore, ithas been suggested to conduct UPD testing in pregnancies with chromosomal aberrations feting ‘lvomosomes 6,7 IL 1,18 and 20[ though t shoul be carefully considered in espet to the decision on the further progress ofthe pregnancy [1 7. Detection of UPD inthe Era of Prenatal High-Resolution Testing Prenatal UPD detection has become a topic again with the implementation of non-invasive prenatal esting (NIFT) onthe si of NCS bose anaes of fetal cell fee DNA in maternal erm Infact. the st ase of UPDhave already been proven afer detection of samy CPM by NIP (01 ‘vn unpublished data) and duc to he api increasing application of NIPTin preganey management the deletion of a rowing numberof UPD an be expectedLUPD ean also be denied incidentally by high-reslution ass seeking genomic causes of fetal snallormatons and disses [12,2]. As netoned before, LOH tte inde UPD [2] and this _Reetic easton con theron help to deni homer ast for ecesve pathogenic rants ‘or stub inheritance of imprinted regions (eg KOSH [5 On te ther han iidental UPD ‘tection by prenatal NGS analysis might india (mosaic) chromosomal strange as the cause of ‘lial fetus Wheres UPDIs dectabe by LOHstrtches obtained high-resolution assaysin single pint, LP would expe detection. However UPRD sin principle ao dtetale by SNP micrseey of [NGS analyses, but UPHD megons are commonly identified bythe comparison ofthe pation genotypes ‘with those fom the parents riekased analysis incase of NCS), "The application of high-esclution assays in prenatal management ignicnty improves the detection rte oe genni alterations causing aberrane phenotypes lr reve [11 15)-On tether hand he scertainment of an creasing amnt of gene daa acompanie bya greing ember ‘Fncdenal ings, comprising bth cbvieusly pathogenic variants aswel as variants of unknown ‘linia significance Inthe end, these data might become dificult interpret and to advice. ‘These considerations also refer ko UPDs: the incidental identi of UPD affecting & region hasboving clinically eelovantinpined genes requss the coenprchensive and tateobtheart ‘ounselng ofthe fami: The sitaton firth comp incase a chroma egon of eee impening ats clic eleranceisafced. Anexample isthe prenatal dentition of ups 6k fe NIP or hich the clinical emsaguence re curen fot presiabl[17], However even in cee {UPD of chromosomal ns hich reno associated wilh clical phenotypes deo distrbed imprinting, thers the ret homoaygoity fora esi pathogenic alle which cannot estimate, “Ts the wentfcton ofa UPD who obvious clini eevanee might contribute to ancy of the adeice=seking coupe without providing sea knowledge Despite these challenges in penal diagnosis the detection of UPD by highesauton assays also provides further knowledge on UPD an is functional elevance, Hallows the identistion of “cpmenial UPDs and thereby narrows down clnlly evant npeinterepons nl unipaental “Sisomic eons might help o Ment new genes nd cessive variants. contrast single cts tests(eg. TRS) the igh-thvoughput and high-resolution assays allow th genome-wide enificaton ‘of segmental) UPD. ‘8 Conclusions and Outlook ‘The implementation of next generation genomic assays with consderable high-resolution (eg. microarrays, next an tied generation sequencing, genome imaging) in the gene agnostic seting has aleay been conde nd numerous stdin and pubiatons have proven the power, ‘appropriateness and labity of the diferent methods io deny SNVsand copy nuraber variants (CNV) se well as epigenetic alterations In akition they allow the entiation of UPD, tery he funcional and lina elevanc ofthe whole chromosome aswel segmental UPDs canbe ict, In parallel tothe validation of next generation genomic assays in postnatal genetic dlgnostcs thelr appliation in prenatal management hasbeen pursued. not, prenatal chromosome mcrae nals] and NIPT are meanwhile widely used screening tos, and prenatal NGS to ie rmonoetic causes of fetal malformations isin establishment [1 With he increased application of these approaches as isin tests the numer ficial ings wil Further increase and these findings comprise UFDsas wel, However asshowa i ths ree the nid enteton af UPD ‘soften dificult manage, and shoul therefore be eed na comprehensive mullcplinary ‘management appro, parc stahould nea highly lranound a lic atte Temust be embedded in goneticounsling, and ethical issueshave tobe adresse so that the pationts ‘can finally comet sell-determined decison. CCencalpreestcourselingisaiso necessary to inform onthe benefits, imitations and digpesie scopect genetic tet.Funding Th authors sppora bythe Detche Forschung (DFG, EGHIOAS ov Copy uber vacant KOsit ——_Kagam-Oyatsyadame MSMLPA.—_Metyatonpcic multpe ato epndent probe mpiiston Nc Next gone sequencing Nirr Nownesie prenatal ttn sr ‘Single macie polymorph ur Unipare ierny {UPN ripe etry UMD Unipaetal xs [Urban Segmental UPD alld pal UPD) 1. Tayo Ane net conap:Unptentloay antl fc, om A | Mad Get 6137145. forne (PN 2 Egg, TS Ls Biting, K: Kot D Masa ipreta disomy in promt gnosis Tee Mat Mel. 2015, 21, 7-47 (Crouse Ds] 3. _ Kote. Complex and seri unpnsal disoy(UPD Review ales om ie hon omen J Me Gm 201,38 497-87. [al Pub 4. Dechert LE-Katwama 8 Lehman, Awe £ Harn Lagan SE Hla Hated ‘Sl [Ps Enns ta inc presentation of 2 transient nna ables els (32 TNDND) and gency phenotype cea nan ination shot of patents Dar 3, 96,7576 {ios rab 5. Exguman, Osho Bs Dik Thumas Wi Kner D; Abt Begin, M Kart Bey Baiting, K The mater parental dn of creme psa pre fp tan Seni? Mal Got Gane Me 201756647, [crn uses] (6 Nakamura Aya, Ks Ops Kava HL; Nalabayahs Ks Matas, Ke Opt, T= Kura K: Flan M: Kogan M.A ive of putea npr samy fr ehomsome 7 scat wlth sve J Cot 208 5 S63] Watsing. EL; Brion, Fo Loko Satize, O; OCaml, SM: Solem, Js Bick J: Canon, AP: ‘Cyzanowsh, KH, Dav LH, Das KP etal: Diagnose and maragemento Sve Rusloyntome Fiatinematonl consent. Nat Re Endrin 20,13 124 [vost] Bele Fs Kah IM: Man, As Fest AC Bok: Fee, CB: Boonen, SE Cle, T Baker R: ‘Becki Wasa syne: Anerson snus sanantNt Re Endrin 16, s-2 [crse] 3. Kap, KO Brg C; Dt, A; Gel A;Hoopman M; A, H-Nove alan materal sonographic ndings cons xe of eth Wade yee, Pot Dig A008, 35, 3498, cs] 1 lima: ter Maines, DO. Ma J: Holder sel EL Meinl npr lacy of vero 1 a patent with Ser Roselyn, Mad, Cem 208 45, 36-98 [cota] 1, San S; Mattar, K Nagas Kikuchi Ty Nakata K; at, K Fulani M Kapa MC ‘ulin inpinting ttane A femaledaminantphenimenoe? | ane. Cont 2016), 75-78 [Cros bes12, Glaser Kaetech, G2 Albrecht, Bh Eagermann, Trach, Ms Miter Ds Movlt, 5: ‘an Ravenswani Arts, CM, Schl S; SB Wiemann Bing Ka Moka an clink ‘sin patent ith Kempe pdr Cl Gt 2038, 95 181186 [cre Ps 15, Tne, Looe K: Mbeki DJsDuvies Temple K Temple re posing tbe ‘cognition fan undergnose hese 4 npr are: An aaa 51 pbs css FFM Get 206, 51,4501 foal [es] 1M. Brak Begemann M; Dey D Eat M:Fggeman T Molec characterization ftemplesyde fas wh 42 epmtations Ear Mos Gen 3006, DMT cre 15. Dagh, AL; Mu, Wiliams, CA. Anpinon Spud Adam, ALP, Aringer, HLL, Pago, RA, Walls SE. Bean CIM, Sephos Ky Amen, AEs: Geers Seat WA USA 1 16. Driscoll, Mil, HL Swan SCs SB Pali Spon Adam, NLP. Ainge, AL Pagon, RA, Walle SE, Boa JH, Stphen K, Aruna, A, Edn; GanceiesR Seale WA, 17, Scheer, Ry Begoman M, Sve, L: Meche, Ds Rabe Meyer Geach M Schubeet R german. Maternal nipuretl dom of homeo I apna: lineal ate ator ne y (iden hoy Io sic thin By plat Cl Geet 2972.41 [ce] 14, te, Yga HL Nika, Nohara A Matsa K; Nun, NalayasK; Yaz. Fake T Oka Atal. Molecular and clin analyses topes eth UPDXT mat detect! by screening patents wth SiverRasels)ndrime phn ot sng ado. [Mal Cot 201.58, S148 fcr (Pa 19, Mannan G:Ratepe Me Man, De Sint Lhe; La A Abed, SF Bl, Rs Chopin inertial onsen Stent Rat Be. 208 1476-50 [Cre] [AL Mulehndan Bh EJ: Lan AMPs amo, Ney K: Copp KW: Ebeakt M: Eggrmann ‘gmt ile Gon Md. 206, 1, 30515 [ol] 21. Kant S;Nakamue,A Ioe TMatr, K Hora, Re Wak Kaka, K akin Tena TMizr eal eal ipl Dey fr Chrno 2 Pysalan Eel {Chace f Five Paes Clin, Er, ee, 8, 203 2-28 [Cee 22 Vw; Abr, My Ad KG, Ds Mel MMi, E Sai; Shon Zargazs, M Haman apply nein ori al tal: Ea. Ml Mae 199625, 167-175, 23, Hina T Mel M; Akin Ks Freman S; Sherman S Reiman an mara peepee olnjucin Moll stn fae 1 Am H.C 1995, 5786-4 24. Kotor D:LteronnC Unpentalemy(UPD) ther ha 5 hentypes a bight ‘An el Gen 08,135 28-8 (Ces [Pes 25. Chamero, §; Statmann,S; Brow, Fi Bagmann, Me Each Ms Grau Neumann aan, Me Netshine, ,Eggemann, Formation of wpa by tron sc: SNP ay provides nw insights in cvomenomalndsncton. Cpe 271,26 foros (Pe, 24 Ui Cytngeetcontbuon unpre omy (UPD) All. Cont a3 & (Cr 27, DalGause, shin AM Asbury: Taeh MLK: Desk, KL Rc Dagon sting formant lacey: A points to cooker sone fom he Aeron allege of Medi Genetics and Geom (ACME). Gow, Mot 20m 2,1139-18, [Coser 2%. Yip AY. Unpanntldsomy in Robertsonian anlocations: Sage for unparental somy ein Tas Pate 204, 3, 98407. [Cosster Ute T Eves Es Ham AB; Krsyahon, Ng Ms We, Ay Manvejan, tS perme ‘marker chooses and pet cy bane son ol. | Hee Chm 201,588 (Coke) aL Sonne Li Bgemann Mi Micky, Ds Gronskow K Tames, 2 Mahe ER Temple LK Monk: B isi A-Linga Atal Reet Avance inlnplting Dona Ci Con 2017, 4,218 es] 51, Spence, FE: Pesca RG: Grog GM: ila FLL, DE: Hemant, [Plc MS ‘tren WE; Benet AL Uniparntal dsony anwchais fr hanan pe sense A Hum ot 985,02,217.206tneypstt aie of Meche Grabe syme: Rept ofa ase Paitin 007,32, 19-182 [mas] 58, Keamey, HM Ream JB; Canin: Diagnostic impliaton of eee amazy sity det by SNP-based mcrtys: Consanguiy, upretl som. and eave siglo mutations heat M200 31, 395-41 fos Ps 34, Schnnier G; Stuns, St; Dae, A; MaeHalann, U; Epgenan, Tz Pols, Rese, Os Bonin M LUPDIct A too or detection of sano In PENN feos Using SNP mies sift 9,29, 962-156 [Cl [Nes] 55. 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