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Uniparental Disomy (UPD) Tech Review.Indd UUniparentalniparental DDisomyisomy (UPD)(UPD) IIntroductionntroduction iiss eexpressedxpressed onlyonly wwhenhen iitt iiss inheritedinherited fromfrom thethe father.father. IIff tthehe ffather’sather’s TThehe 4466 cchromosomeshromosomes iinn eeachach ccellell ooff tthehe hhumanuman bbodyody ccanan bbee ddividedivided SSNRPNNRPN ggeneene iiss absentabsent ddueue ttoo mmaternalaternal UPDUPD 115,5, tthehe cchildhild wwillill bebe iintonto 2233 ppairs.airs.1 NNormally,ormally, oonene cchromosomehromosome ooff eeachach ppairair iiss iinher-nher- aaffectedffected wwithith PPrader-Willirader-Willi ssyndrome.yndrome.4 PParent-specificarent-specific iimprintingmprinting iitedted ffromrom tthehe mmotherother aandnd oonene ffromrom thethe ffather.ather. UUniparentalniparental ddisomyisomy aandnd cconsequencesonsequences ooff UUPDPD aarere kknownnown fforor mmaternalaternal cchromosomeshromosomes 77,, ((UPD)UPD) iiss aann aatypicaltypical iinheritancenheritance ppatternattern iinn wwhichhich bbothoth mmembersembers ooff a 114,4, aandnd 115,5, aandnd ppaternalaternal cchromosomeshromosomes 66,, 111,1, 114,4, aandnd 115.5.2 ssingleingle ppairair ooff cchromosomeshromosomes aarere iinheritednherited ffromrom oonene pparent.arent.2 AAnothernother cconcernoncern wwithith UUPDPD iiss tthehe rriskisk fforor aann aautosomalutosomal rreces-eces- UUPDPD iiss ccommonlyommonly iinitiatednitiated wwhenhen cchromosomeshromosomes ffailail ttoo sseparateeparate ssiveive ddisorder,isorder,22,3,3 suchsuch aass ccysticystic ffibrosisibrosis ((CF).CF). IInn typicaltypical MMendelianendelian pproperlyroperly dduringuring tthehe ddevelopmentevelopment ooff aann eegggg oorr sspermperm iinn mmeiosis.eiosis. iinheritancenheritance ooff aann aautosomalutosomal rrecessiveecessive ddisorder,isorder, bbothoth pparentsarents mmustust bebe TThehe aabnormalbnormal sseparationeparation iiss ddueue eeitherither ttoo nnondisjunctionondisjunction oorr tthehe ppres-res- ccarriersarriers ooff a ddisease-causingisease-causing mmutationutation fforor tthehe ddiseaseisease ttoo ooccur.ccur. UUPDPD eencence ooff a cchromosomehromosome ttranslocationranslocation ((fusionfusion ooff oonene ppartart ooff a cchromo-hromo- mmayay rresultesult iinn tthehe ppresenceresence ooff a rrecessiveecessive cconditionondition wwhenhen oonlynly oonene ssomeome oontonto aanothernother cchromosome).hromosome). NNondisjunctionondisjunction lleadseads ttoo a ttrisomyrisomy pparentarent ccarriesarries a mmutation.utation. IInn tthishis ccase,ase, a cchildhild inheritsinherits ttwowo ccopiesopies ((anan eextraxtra ccopyopy ooff a cchromosome)hromosome) oorr mmonosomyonosomy ((aa mmissingissing ccopyopy ooff ooff a mmutation-carryingutation-carrying ggeneene ffromrom a ssingleingle pparent.arent. TThishis hhasas bbeeneen a cchromosome)hromosome) iinn tthehe cconceptus.onceptus. A cchromosomehromosome ttranslocationranslocation iinn ddocumentedocumented fforor sseveraleveral ggeneticenetic cconditions.onditions.2 tthehe eegggg oorr sspermperm ccanan rresultesult iinn a ccompleteomplete ttrisomy,risomy, a ppartialartial ttrisomy,risomy, oorr mmonosomyonosomy ((extraextra oorr mmissingissing portionsportions ooff a ssingleingle cchromosome)hromosome) TThehe cchancehance tthathat UUPDPD eexistsxists wwhenhen a ttrisomy,risomy, mmosaicismosaicism ((partialpartial ttri-ri- iinn tthehe ffertilizedertilized eegg.gg. IInn aann aattemptttempt ttoo rregainegain a bbalancedalanced cchromo-hromo- ssomy),omy), oorr bbalancedalanced ttranslocationranslocation aarere oobservedbserved iinn pprenatalrenatal ddiagnosisiagnosis ssomeome nnumber,umber, a ssecondecond eeventvent ooccursccurs ttoo ““rescue”rescue” tthishis iimbalance,mbalance, rrangesanges ffromrom llessess tthanhan 11%% ttoo aapproximatelypproximately 666%.6%. DDueue ttoo thethe bbroadroad eeitherither bbyy llossoss ooff aann eextraxtra cchromosomehromosome iinn tthehe trisomictrisomic ccellell oorr bbyy thethe rrangeange ooff rriskisk andand ggeneticenetic ccounselingounseling iissues,ssues, UUPDPD testingtesting sshouldhould bebe dduplicationuplication ooff a cchromosomehromosome iinn tthehe mmonosomiconosomic ccell.ell. UUPDPD ooccursccurs cconsideredonsidered iinn tthehe ffollowingollowing ssituationsituations2: wwhenhen tthishis rrescueescue eeventvent lleaveseaves tthehe ccellell wwithith a cchromosomehromosome ppairair tthathat ooriginatedriginated ffromrom oonlynly oonene pparentarent ((FigureFigure 11).).2 • PPrenatalrenatal ddetectionetection ooff cchromosomalhromosomal mmosaicismosaicism oorr ccompleteomplete ttrisomyrisomy iinn a cchorionichorionic vvillusillus ssampleample ((CVS)CVS) fforor cchromosomeshromosomes 66,, 77,, 111,1, 114,4, 1155 UUniparentalniparental ddisomyisomy hhasas bbeeneen rreportedeported fforor tthehe mmajorityajority ooff cchromo-hromo- • PPrenatalrenatal ddetectionetection ooff a bbalancedalanced RRobertsonianobertsonian ttranslocationranslocation iinvolv-nvolv- ssomeome ppairsairs wwithoutithout aanyny ddefinitiveefinitive cclinicallinical ooutcomeutcome22,3,3; hhowever,owever, iingng cchromosomeshromosomes 1144 oorr 1155 UUPDPD fforor ccertainertain cchromosomehromosome ppairsairs rresultsesults iinn rrecognizableecognizable ggeneticenetic • IIndividualsndividuals ppresentingresenting wwithith ffeatureseatures cconsistentonsistent wwithith ddisordersisorders kknownnown 2 cconditions.onditions. TThesehese cchromosomeshromosomes hhaveave ggenesenes tthathat aarere iimprinted.mprinted. ttoo bbee aassociatedssociated wwithith UUPPD2 IImprintedmprinted ggenesenes aarere ppreferentiallyreferentially tturnedurned oonn ((expressed)expressed) oorr ooffff • FFetusetus oorr ssymptomaticymptomatic ppatientatient wwithith a ddee nnovoovo ssupernumeraryupernumerary mmark-ark- ((notnot eexpressed)xpressed) ddependingepending oonn wwhichhich pparentarent ppassesasses tthehe ggeneene ttoo tthehe eerr cchromosomehromosome ((SMC)SMC) iidentifieddentified bbyy cchromosomehromosome aanalysisnalysis5 ooffspring.ffspring.2 OOnene eexamplexample iiss a sspecificpecific ggeneene (SSNRPNNRPN) oonn cchromo-hromo- ssomeome 1155 iinvolvednvolved iinn tthehe PPrader-Willirader-Willi ssyndrome.yndrome. TThehe SSNRPNNRPN ggeneene TTestest OOptionsptions TTestingesting fforor UUPDPD iinvolvesnvolves DDNANA aanalysisnalysis tthathat ccomparesompares mmarkersarkers oonn a pparticulararticular cchromosomehromosome bbetweenetween tthehe mmother,other, ffather,ather, aandnd cchildhild ((oror ffetus).etus). LLabCorp’sabCorp’s UUPDPD ttestest iiss aavailablevailable fforor aallll cchromosomes.hromosomes. SSinceince tthishis ttestest ccanan rrevealeveal nnonpaternity,onpaternity, iinformednformed cconsentonsent ppriorrior ttoo ttestingesting sshouldhould bbee oobtained.btained. AAnn aalternativelternative ttest,est, rrequiringequiring a ssampleample ffromrom oonlynly tthehe cchild,hild, oorr ffetus,etus, iiss aavailablevailable ttoo iidentifydentify iimprintingmprinting ddefectsefects fforor cchromosomeshromosomes 1144 aandnd 115.5. TThishis ttestest eexaminesxamines a sspecificpecific ggeneene oonn cchromosomehromosome 1144 ((MEG3)MEG3) oorr cchromosomehromosome 1155 (SSNRPNNRPN) tthathat iiss iimprintedmprinted ((methylated)methylated) ddiffer-iffer- eently,ntly, ddependingepending oonn wwhetherhether iitt wwasas iinheritednherited ffromrom tthehe mmotherother oorr tthehe ffather.ather.66,7,7 TThehe cchromosomehromosome 1155 mmethylationethylation aanalysisnalysis iidentifiesdentifies aapproximatelypproximately 778%8% ooff ccasesases ooff AAngelmanngelman ssyndromeyndrome aandnd mmoreore tthanhan 999%9% ooff PPrader-Willirader-Willi ssyndrome.yndrome.8 TThehe cchromosomehromosome 1414 methylationmethylation ttestest iidentifiesdentifies aallll ccasesases ooff mmaternalaternal UUPD14PD14 aandnd ppaternalaternal UUPDPD 11446; hhowever,owever, iitt ddoesoes nnotot iidentifydentify tthehe uunderlyingnderlying ggeneticenetic mechanism,mechanism, Figure 1.—Common Mechanisms Leading to UPD2 wwhichhich ccouldould bbee aann iimprintingmprinting ddefect,efect, ddeletion,eletion, oorr UUPD.PD.7 Uniparental Disomy Profi le . 470054 Uniparental Disomy of Chromosome 14 (UPD 14) . 470060 CPT 83891; 83894; 83900; 83912 CPT 83891; 83901; 83894; 83912 Special Instructions A separate test request form must be completed for Specimen Whole blood, amniotic fl uid (direct or cultured) or LabCorp each family member submitted. The patient’s name, age, and relevant buccal swab kit (The buccal swab collection kit contains instructions clinical and family history should be included on the corresponding test for use of a buccal swab.) request form. Please include chromosome pair to be studied. Blood Volume 7 mL whole blood, 10 mL amniotic fl uid, or LabCorp buccal specimens from both patents should be submitted, although a specimen swab kit from one parent may be suffi cient in some cases. Minimum Volume 3 mL whole blood, 5 mL amniotic fl uid, or two Specimen Whole blood or amniotic fl uid buccal swabs Volume 7 mL whole blood or 10 mL amniotic fl uid or amniocyte cul- Container Lavender-top (EDTA) tube or yellow-top (ACD) tube, ster- ture ile plastic conical tube or two confl uent T- 25 fl asks for fetal testing, or Minimum Volume 3 mL whole blood or 5 mL amniotic fl uid LabCorp buccal swab kit Container Lavender-top (EDTA), green-top (heparin) or yellow-top Storage Instructions Maintain at room temperature or refrigerate at 4°C (ACD) tube, sterile plastic conical tube or two confl uent T-25 fl asks for Causes for Rejection Hemolysis; quantity not suffi cient for analysis; fetal testing improper
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