UUniparentalniparental DDisomyisomy (UPD)(UPD) IIntroductionntroduction iiss expressedexpressed onlyonly whenwhen itit isis inheritedinherited fromfrom thethe father.father. IfIf thethe father’sfather’s TThehe 4466 cchromosomeshromosomes iinn eeachach ccellell ooff thethe humanhuman bodybody cancan bebe divideddivided SSNRPNNRPN genegene isis absentabsent duedue toto maternalmaternal UPDUPD 15,15, thethe childchild willwill bebe iintonto 2233 ppairs.airs.1 NNormally,ormally, oneone chromosomechromosome ofof eacheach pairpair isis inher-inher- aaffectedffected wwithith PPrader-Willirader-Willi ssyndrome.yndrome.4 PParent-specificarent-specific iimprintingmprinting iitedted fromfrom thethe mothermother andand oneone fromfrom thethe father.father. UniparentalUniparental disomydisomy 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 isis commonlycommonly initiatedinitiated wwhenhen cchromosomeshromosomes ffailail ttoo sseparateeparate ssiveive disorder,disorder,22,3,3 suchsuch asas cysticcystic fibrosisfibrosis (CF).(CF). InIn typicaltypical MendelianMendelian pproperlyroperly dduringuring tthehe ddevelopmentevelopment ooff aann eegggg oorr sspermperm iinn mmeiosis.eiosis. iinheritancenheritance ooff aann aautosomalutosomal rrecessiveecessive disorder,disorder, bothboth parentsparents mustmust 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 resultresult inin thethe presencepresence ofof a recessiverecessive cconditionondition wwhenhen oonlynly oonene ssomeome oontonto aanothernother cchromosome).hromosome). NNondisjunctionondisjunction lleadseads ttoo a ttrisomyrisomy pparentarent carriescarries a mutation.mutation. InIn thisthis case,case, a childchild inheritsinherits twotwo 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 monosomymonosomy (extra(extra oorr missingmissing portionsportions ofof a singlesingle chromosome)chromosome) TThehe cchancehance tthathat UPDUPD existsexists 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 number,number, a ssecondecond eeventvent ooccursccurs ttoo ““rescue”rescue” tthishis iimbalance,mbalance, rrangesanges ffromrom lessless thanthan 1%1% toto approximatelyapproximately 66%.66%. DueDue toto thethe broadbroad eeitherither byby lossloss ofof anan extraextra chromosomechromosome inin thethe trisomictrisomic cellcell oror byby thethe rrangeange ooff rriskisk andand geneticgenetic counselingcounseling issues,issues, UPDUPD testingtesting shouldshould bebe dduplicationuplication ooff a cchromosomehromosome iinn tthehe monosomicmonosomic cell.cell. UPDUPD occursoccurs 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 disomydisomy hashas beenbeen reportedreported 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. TheseThese chromosomeschromosomes havehave ggenesenes tthathat areare imprinted.imprinted. ttoo bbee aassociatedssociated wwithith UUPPD2 IImprintedmprinted genesgenes 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) onon chromo-chromo- 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 chromosomechromosome 1515 (SSNRPNNRPN) tthathat iiss iimprintedmprinted ((methylated)methylated) ddiffer-iffer- eently,ntly, dependingdepending onon whetherwhether itit waswas 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% ofof PPrader-Willirader-Willi ssyndrome.yndrome.8 TThehe chromosomechromosome 1414 methylationmethylation ttestest iidentifiesdentifies aallll ccasesases ooff mmaternalaternal UUPD14PD14 aandnd ppaternalaternal UUPDPD 11446; hhowever,owever, iitt doesdoes notnot identifyidentify thethe underlyingunderlying geneticgenetic 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 container; one buccal swab Storage Instructions Maintain specimen at room temperature. Do not Use Methylation-specifi c PCR is used to amplify divergent lengths of freeze. the methylated and unmethylated MEG3 DMR region on chromo- Causes for Rejection Frozen or hemolyzed specimen; improper con- some 14q32 in a single reaction and thereby accurately identify the tainer normal, maternal UPD14 and paternal UPD14 patterns. Use Establish the parent of origin for syndromes that may result from Limitations Molecular analysis of the MEG3 gene is perfomred by single parent inheritance of both homologues of a specifi c chromo- methylation-specifi c PCR and gel electrophoresis. This assay detects some pair. The best examples of this are Prader-Willi and Angelman all cases of maternal UPD14 and paternal UPD14 arising from UPD, syndromes in which maternal and paternal uniparental disomy (for microdeletions, and imprinting defects but does not defi ne the nature chromosome 15), respectively, are reported. Other examples include of underlying genetic defect. Molecular-based testing is highly ac- Russell-Silver syndrome (chromosome 7) and Beckwith-Wiedemann curate, but as in any laboratory test, rare diagnostic errors may occur. syndrome (chromosome 11). This procedure may be considered by Medicare and other carriers as Limitations This procedure may be considered by Medicare and other investigational and, therefore, may not be payable as a covered benefi t carriers as investigational and, therefore, may not be payable as a cov- for patients. ered benefi t for patients. Methodology Methylation-specifi c polymerase chain reaction and gel Methodology Analysis of VNTRs and AMPFLPs by polymerase chain electrophoresis reaction (PCR) and gel electrophoresis. UPD Syndromes2 Angelman and Prader-Willi Syndromes, DNA Analysis Angelman Syndrome. Associated with severe mental retardation, absent ...... 511210 speech, ataxia, seizures, paroxysmal laughter. Approximately 3% to 5% of CPT 83891; 83894; 83900; 83912 cases result from paternal UPD 15. Related Information Fluorescence in situ Hybridization (FISH), Mi- Beckwith-Wiedemann Syndrome. An overgrowth syndrome associated with crodeletion Syndromes macroglossia, organomegaly, omphalocele, and Wilms tumor. About 20% Synonyms Prader-Willi and Angelman Syndromes, DNA Analysis have paternal UPD for the distal arm of chromosome 11. Special Instructions Please provide pertinent fi ndings, family or per- Maternal UPD 14. Common features are short stature, hypotonia, hyperexten- sonal, of mental retardation, autistic behaviors, developmental delay sible joints, mildly dysmorphic features, developmental delay, and precocious and obesity. puberty. Specimen Whole blood, amniotic fl uid or LabCorp buccal swab kit Paternal UPD 14. Features include mental retardation, short limb dwarfi sm (Buccal swab collection kit contains instruction for use of a buccal with small thorax, respiratory diffi culties, dysmorphic features, and scoliosis. swab.) Note: Submission of maternal blood is required for fetal test- Prader-Willi Syndrome. Characterized by severe hypotonia in infancy, followed ing. by excessive eating, obesity, cognitive impairment, behavior problems, and hypo- Volume 7 mL whole blood, 10 mL amniotic fl uid, or LabCorp buccal gonadism. Approximately 28% of cases are a result of maternal UPD 15. swab kit Russell Silver Syndrome. Associated with pre- and postnatal growth retarda- Minimum Volume 3 mL whole blood, 5 mL amniotic fl uid, or two tion and dysmorphic features. About 10% of patients have maternal UPD for buccal swabs chromosome 7. Container Lavender-top (EDTA) tube, yellow-top (ACD) tube, sterile Transient Neonatal Diabetes Mellitus. About 20% of cases have UPD of plastic conical tube, or two confl uent T-25 fl asks for fetal testing, or paternal chromosome 6. LabCorp buccal swab kit Storage Instructions Maintain specimen at room temperature or re- RReferenceseferences frigerate. Do not freeze. 11.. NNussbaumussbaum RRL,L, McInnesMcInnes RR,RR, WillardWillard HF.HF. GGeneticsenetics iinn MMedicineedicine. 6th6th ed.ed. NewNew York,York, NY:NY: Causes for Rejection Frozen or hemolyzed specimen; quantity not WW.B..B. SSaunders;aunders; 22001:5.001:5. suffi cient for analysis; improper container; one buccal swab 22.. ShafferShaffer LG,LG, AganAgan NN,, GGoldbergoldberg JJD,D, LLedbetteredbetter DDH,H, LongshoreLongshore JW,JW, CassidyCassidy SB.SB. AmericanAmerican CCollegeollege ofof MedicalMedical GGeneticsenetics sstatementtatement oonn ddiagnosticiagnostic ttestingesting fforor uuniparentalniparental ddisomy.isomy. GGenetenet Use This test will detect all major causes of Prader-Willi and Angelman MMeded. 22001001 MMay-Jun;ay-Jun; 33(3):206-211.(3):206-211. syndrome. These include uniparental disomy (UPD), microdeletions 33.. KKotzototzot DD,, UUtermanntermann GG.. UUniparentalniparental ddisomyisomy ((UPD)UPD) ootherther tthanhan 115:5: PPhenotypehenotype aandnd bbibli-ibli- and imprinting center defects. It is recommended that, in addition to oographygraphy uupdated.pdated. AAmm J MMeded GGenetenet A. 22005005 JJul;ul; 1136(3):287-305.36(3):287-305. this methylation-based test, Chromosome Analysis, High Resolution 44.. CassidyCassidy SB,SB, DykensDykens E,E, WilliamsWilliams CA.CA. Prader-WilliPrader-Willi andand AngelmanAngelman syndromes:syndromes: SisterSister (052027) be ordered to distinguish between the underlying mecha- iimprintedmprinted disorders.disorders. AAmm J MMeded GGenetenet. 2000;2000; 997(2):136-146.7(2):136-146. 55.. SStarketarke HH,, NNietzelietzel AA,, WWeiseeise AA,, eett aal.l. SSmallmall ssupernumeraryupernumerary mmarkerarker cchromosomeshromosomes ((SMCs):SMCs): nisms. GGenotype-phenotypeenotype-phenotype ccorrelationorrelation aandnd cclassification.lassification. HHumum GGenetenet. 2003;2003; 114:51-67.114:51-67. Limitations Approximately 11% of Angelman syndrome cases aris- 66.. MurphyMurphy SK,SK, WylieWylie AA,AA, CovelerCoveler KJ,KJ, etet al.al. EpigeneticEpigenetic detectiondetection ofof humanhuman chromosomechromosome ing from UBE3A mutations will not be detected by this test. This 1144 uuniparentalniparental ddisomy.isomy. HHumum MMutatutat. 20032003 Jul;Jul; 222(1):92-97.2(1):92-97. procedure may be considered by Medicare and other carriers as in- 77.. CCassidyassidy DDB,B, BBeaudeteaudet AAL,L, KKnollnoll JJHM,HM, eett aal.l. AASHG/ACMGSHG/ACMG rreport.eport. DDiagnosticiagnostic ttestingesting vestigational and, therefore, may not be payable as a covered benefi t fforor Prader-WilliPrader-Willi andand AngelmanAngelman syndromes.syndromes. ReportReport ofof thethe ASHG/ACMGASHG/ACMG testtest andand technologytechnology ttransferransfer committee.committee. AAmm J HumHum GenetGenet. 1996;1996; 58:1085-1088.58:1085-1088. for patients. 88.. GeneReviewsGeneReviews ofof AngelmanAngelman Syndrome.Syndrome. AvailableAvailable at:at: www.genetests.org.www.genetests.org. AccessedAccessed Methodology Methylation-sensitive PCR and gel electrophoresis NNovemberovember 88,, 22005.005.

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