GENETIC TESTING AND SCREENINGThe Spectrum of Utility in Genetic Testinghigh utility low utility potentiallyharmfulMEN2HemochromatosisColo-rectal CancerBreast/ovarian CancerAlzheimerDiseaseHighly effective & acceptablePre-symptomatic interventionNo effective treatmentProgression of Understanding in Genetic Testing for Clinical DisordersMethods of Genetic Diagnostic TestingaChromosomal analysis (karyotype)`metaphase analysis, G(Giemsa) banding`prometaphase (high resolution) analysis`special stains (banding) studies`breakage studies`sister chromatid exchangeaMolecular cytogenetics`fluorescent in-situ hyridization (FISH)`chromosome paintingMethods of Genetic Diagnostic Testing(con’t)aLinkage studies`restriction fragment linked polymorphisms (RFLP)`polyorphic microsatellite analysis`CG repeats`variable number tandem repeats (VNTR)`chromosome polymorphismsMethods of Genetic Diagnostic Testing(con’t)aQuantification of trinucleotide repeats`Southern blotaSite specific confirmational polymorphisms (SSCP)`deletional screening`point mutationsaProtein truncation assayMethods of Genetic Diagnostic Testing(con’t)aMultiplex polymerase chain reaction (PCR)`major gene rearrangements / deletionsa Direct sequencingaBiochemical studiesaImmunofluorescent protein studiesaCombination strategiesPractical IssuesaDNA bankingaSpecimen requirementsaRetrieving past specimensGenetic ScreeningDefinitiona Genetic screening`A search in a population for ‘healthy ‘ persons that possess a genotype which:1. is associated with a predisposition to a disease2. May lead to a disease in their descendants3. Produce other variants not known to be associated with diseaseaScreening does not equal testing. (The methods are the same, the difference is “why” the tests are done.Methods of Genetic ScreeningaDisease stateaAltered cellular or metabolic functionsaAltered gene productaChanges in the DNA (molecular changes)Objectives of ScreeningaTherapyaPreventionaIdentify at risk individuals / couplesaSource of epidemiologic dataPrinciples of ScreeningaSensitivity : all positives detected (no false negatives)aSpecificity : False positives minimizedLevels of ScreeningaIndividualaSelected PopulationaGeneral PopulationIndividual Screeninga Lead screening in a childSelected Population Screeninga Heterozygote (carrier)`parents of child with CF`mothers of boys with Fragile - XaEthnic specific`certain ethnic groups are at such a high risk for a particular condition that selected screening is warranted (low frequency in general population)Ethnic Specific ScreeningaAshkenazi (Eastern European) Jewish`PanelaFrench - Canadian`Tay-SachsaAfrican`Sickle cellaMediterranean / South-East Asian`hemoglobinopathiesAshkenazi DNA Panel83%1/90Fanconi Anemia95%1/10Gaucher97%1/25Cystic Fibrosis98%1/40Canavan95%1/30Tay SachsDETECTION RATEBY DNA ANALYSISCARRIER FREQUENCY(Approximate)DISEASEPopulation ScreeningaNewborn Screening = prototypePrerequisites for a Population Screening ProgramaCondition sufficiently frequent in screened populationaCondition serious or fatal without interventionaCondition must be treatable or preventableaEffective follow-up program possiblePrerequisites for a Population Screening ProgramaScreening and management must be cost-effectiveaSpecimens must be easy to collectaAnalysis must be simple, reliable, reproducible, and lend itself to mass screeningaAnalysis should have high sensitivity (with some ‘give’ in specificity) Types of Population ScreeningaNewborn screening`PKUaHeterozygote (carrier) screening`Tay-SachsaPrenatal screening`AFP, Triple screen aPresymptomatic (susceptibility) screening`(?) Breast CancerOther Types of Potential Population ScreeningaForensic screeningaSusceptibility screeningIssues in Genetic Screeninga Confidentialitya Right not to knowa Genetic discriminationa Whose information is