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NIPTNon-InvasivePrenatalTestWhatarethegoalsofNIPT?ShouldNIPSbeofferedtoallpregnantpatients?ACMGrecommends:-InformingallpregnantwomenthatNIPSisthemostsensitiveandreliableoptionfortraditionallyscreenedaneuploidiesinvolvingchromosomes13,18and21Cell-FreeDNA(cfDNA)•SmallFragments(<200bp)ofDNAInMaternalCirculation•MaternalFraction•Adipocytes•WhiteBloodCells•FetalFraction•PlacentalCells(Trophoblasts)inMaternalCirculation•10-15%ofTotalcfDNAinMaternalPlasma,After10WksofGestation•WhichOne:cffDNAorcfDNA?AJOG2015;SMFMPubliationCommitteeAvailablecommercialNIPTtestingEurope-Prenatest-LifeCodexx-IONAtest-PremaithaHealthChina-NIFTYTest–BGIUSA-HarmonyTest-AriosaDiagnostic,SanjoseCalifornia-MaterniT21PlusTest–SequenomLaboratories,SanDiego-VerifiTest–VerinataHealth-PanoramaTest–NateraSanCarlosCaliforniaDifferentiatingNIPTMethodologiesTrisomyDetectionbyCountingFetalDisomyFetalTrisomyMaternal“FetalFractionofcfDNAIsKeyIn“Counting”=>HigherFetalFractions=>EasiertoDetectTrisomy(Norton,EtAl.2013)HowFetalFractionAffectsSensitivityJustVisuallyCompare!FetalFractionMattersforCountingFetalFractionTooLowToReportIntermediateFetalFraction–DecreasedSensitivityWithCountingMethodologyFetalFractionAdequateToAchieveBestPerformance“AnAneuploidySampleWithALowerFetalFractionHasAHigherProbabilityOfResultingInAFalseNegativeResult.”ThomasMusci,MDPrenatalPerspectives.Volume1,No.22013.Chromosome3Chromosome21CountingSmallerChromosomeLowerFraction(e.g.Chr.21)LargerChromosomeHigherFraction(e.g.Chr.3)Chromosome3Chromosome21ExpectedAmount:20%80%CountingObservedAmount:25%75%HowWouldYouThenAssesstheRatiosforChr.21vs.Chr.18vs.Chr.13?SNP=SingleNucleotidePolymorphism•ADNAsequencevariationoccurringwhenasinglebasepair(nucleotide)-A,T,C,orG–ischanged.•ThesearenormalgeneticchangesthatoccurineverypersonBuffycoat=MaternalDNAPlasma=Maternal+FetalDNASNPSequencingSNPSequencingMaternalGenotypeMaternal+FetalGenotypeFetalGenotypeMaternalbloodSNPapproachUsingtheBuffyCoattoSequenceMaternalGenotypeAlgorithmNIPTTestprocedureTheNIPTTestcanbeperformedfromweek10+0ofthepregnancy.BeforecarryingoutaNIPTTest,thepatientshouldbegivenanultrasoundscantodeterminethegestationalageandtocheckwhetheritisasingletonormultiplepregnancy.ExcellentdetectionrateinsingletonpregnanciesPanoramaVerifiMaternit21HarmonytestDetectionate>99%>99%>99%99.7%T2198%97%96.4%98%T1895%93%92%93%T13LowfalsepositiverateDANSRmethod5timeslowerthanrmpsReliableevenwithheparintreatment•[1]AshoorG,SyngelakiA,WagnerM,BirdirC,NicolaidesKH:Chromosome-selectivesequencingofmaternalplasmacell-freeDNAforfirst-trimesterdetectionoftrisomy21andtrisomy18.AmJObstetGynecol.2012Apr;206(4):322.e1-5.•[2]NicolaidesKH,SyngelakiA,AshoorG,BirdirC,TouzetG:Noninvasiveprenataltestingforfetaltrisomiesinaroutinelyscreenedfirst-trimesterpopulation.AmJObstetGynecol.2012Nov;207(5):374.e1-6.•[3]NortonME,BrarH,WeissJ,KarimiA,LaurentLC,CaugheyAB,RodriguezMH,WilliamsJ3rd,MitchellME,AdairCD,LeeH,JacobssonB,TomlinsonMW,OepkesD,HollemonD,SparksAB,OliphantA,SongK:Non-InvasiveChromosomalEvaluation(NICE)Study:resultsofamulticenterprospectivecohortstudyfordetectionoffetaltrisomy21andtrisomy18.AmJObstetGynecol.2012Aug;207(2):137.e1-8.•[4]SparksAB,StrubleCA,WangET,SongK,OliphantA:Noninvasiveprenataldetectionandselectiveanalysisofcell-freeDNAobtainedfrommaternalblood:evaluationfortrisomy21andtrisomy18....