Genetic Test Guidelines

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    GeneticTest

    Guidelines

    Ashortessayaboutthe

    LabTest,withusefulinformationandtricksto

    faceit!Hopewillbe

    useful

    AlessandroMotta,

    UVVGMedicinein

    English,2ndYear

    1PART

    Akaryotypeisanorganizedprofileofaperson'schromosomes.Inakaryotype,chromosomesarearrangedandnumberedbysize,fromlargesttosmallest.This

    arrangementhelpsscientistsquicklyidentifychromosomalalterationsthatmay

    resultinageneticdisorder.Tomakeakaryotype,scientiststakeapictureof

    someone'schromosomes,cutthemoutandmatchthemupusingsize,banding

    patternandcentromerepositionasguides,itismadebydigitalizationofthe

    pictureandarrangedonspecialdedicatedsoftware.

    Whatweneedtoknow?SomegeneralinfosaboutnormalHumanKaryotype

    Whenexaminingakaryotype,thegeneticistlooksateachindividualchromo-some.Everychromosomehasatypicalsizeandshape;thelocationofthe

    centromereandthelengthofthechromosomearms(thepartsoneithersideof

    thecentromere)arewhatdefineeachchromosomesphysicalappearance:

    parm:Theshorterofthetwoarms qarm:Thelongerarm

    Insomedisorders,oneofthechromosomearmsismisplacedormissing.

    Therefore,geneticistsoftenrefertothechromosomenumberalongwiththe

    lettersporqtocommunicatewhichpartofthechromosomeisaffected.

    (eg:DownsSindrome:(47,XX,+21)

    Henceitisreallyimportantfordiscriminateanormalkaryotypefroma

    pathologicalonethechromosomescounting:

    Aneuploidreferstoanimbalanceinthenumberofchromosomes.Situations

    involvinganeuploidyareoftengiventhesuffix-somytocommunicatewhether

    chromosomesaremissing(monosomy)orextra(trisomy).

    Euploid(andtherelatedterm,polyploid)referstothenumberofsetsof

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    chromosomesanorganismhas.Thus,diploidtellsyouthattheorganismin

    questionhastwosetsofchromosomes(oftenwrittenas2n,withnbeingthe

    haploidnumberofchromosomesintheset);whenanorganismiseuploid,its

    totalnumberofchromosomesisanexactmultipleofitshaploidnumber(n).

    *Justtorehearseonsomecuepoint:humanshave46totalchromosomes(2n)inallcellsexcept

    forsexualcells(spermandovum)thathavehaploidsituation(1n).Autosomalchromosomesas

    inpicturearelistedfrom1-22andsexualchromosomesarenamedjustXandY.

    Now,anormalcountofahumanbeingkaryotypeis2nor46or44+XY.

    Inpathologicalconditionswehavetounderstandifthevariationoncounting

    cameupfromanAneuploidyorfromaPolyploidy:

    ANEUPLOIDY:Itusuallycausesdrasticphenotypiceffectsbecauseitleads

    tounbalancedgenedosage.

    1.Nullisomyisthelossofbothmembersofahomologouspairofchromosomes.

    Itisrepresentedas2n2,wherenreferstothehaploidnumberof

    chromosomes.Thus,amonghumans,whonormallypossess2n=46

    chromosomes,anullisomiczygotehas44chromosomes.(Couldmeansdeathfor

    theorganism)

    2.Monosomyisthelossofasinglechromosome,representedas2n1.A

    humanmonosomiczygotehas45chromosomes.

    3.Trisomyisthegainofasinglechromosome,representedas2n+1.Ahumantrisomiczygotehas47chromosomes.Thegainofachromosomemeansthat

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    therearethreehomologouscopiesofonechromosome.Downsyndromeresult

    fromtrisomyofchromosome21.

    4.Tetrasomyisthegainoftwohomologouschromosomes,representedas2n+

    2.Ahumantetrasomiczygotehas48chromosomes.Tetrasomyisnotthegainof

    anytwoextrachromosomes,butratherthegainoftwohomologous

    chromosomes;sotherewillbefourhomologouscopiesofaparticular

    chromosome.

    POLYPLOIDY:Mosteukaryoticorganismsarediploid(2n)formostoftheirlife

    cycles,possessingtwosetsofchromosomes.Occasionally,wholesetsof

    chromosomesfailtoseparateinmeiosisormitosis,leadingtopolyploidy,the

    presenceofmorethantwogenomicsetsofchromosomes.Itisnormalinplants;

    itisrareinhumansandleadstodeadofthefetus(spontaneousabortions).

    Nowfocusingonlocalchromosomesrearrangementsthataffectthefinal

    numberofcountingwecanfind:duplications,deletions,inversions,and

    translocations.

    Chromosomeduplicationisamutationthatdoublespartofachromosome.Thishasmajoreffectsonthephenotype,possiblybyalteringgenedosage.Segmentalduplicationsarecommonwithinthe

    humangenome.

    Achromosomaldeletionisamutationinwhichapartofachromosomeislost.Thiscauserecessivegenesonthehomologouschromosometobe

    expressedandmaycauseimbalancesingeneproducts. Inaninversion,asegmentofachromosomeisturned180degrees.

    Inversionscausebreaksinsomegenesandmaymoveotherstonew

    locations.Whencrossingovertakesplacewithintheinvertedregion,nonviablegametesareusuallyproduced,resultinginadepressionin

    observedrecombinationfrequencies.

    Intranslocations,partsofchromosomesmovetoother,non-homologouschromosomesortootherregionsofthesamechromo-some.

    Translocationscanaffectthephenotypebycausinggenestomovetonew

    locations,wheretheycomeundertheinfluenceofnewregulatory

    sequences,orbybreakinggenesanddisruptingtheirfunction.

    Bythewaywhatsremarkablefortomorrow:

    HavinganideaofanormalKaryotypelayout Chromosomescountinginnormalandpathologicconditions Describingapathologyaftercountingthechromosomes

    IhopethispartwillbeusefulevenifIwentalittlefurtherforcompleteness

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    2PART

    ThestudyofGeneticDiseasecanbemadebyusingpedigreestoappreciate

    humancharacteristicinheritance.Thereareafewsymbolsweallshouldtake

    caretoremember:

    ***HenceImprettysureshewouldcareaboutsometypicaldiseasethrees

    SoIreportedthemcasebycase,onlythosemoreimportantandwithanexampleofpathology!

    ThisfirstcaseisatypicalAutosomaldominanttraitpicture:

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    Adominanttraitordisorderisonethatsexpressed(ormanifested)inanyone

    whoinheritsthegeneforthetrait.Inhumanpedigrees,autosomaldominant

    traitshavesometypicalcharacteristics:malesandfemalesareaffectedwith

    equalfrequency;thetraitdoesntskipgenerations,ifneitherparentisaffected,

    andusuallynochildisaffected.

    Typicalautosomaldominantdisorders:achondroplasia,polydactyly,Marfan

    syndrome,Huntingtondisease.

    Autosomalrecessivetraits:disordercanskiponeoremoregenerations;

    affectedchildrenareborntounaffectedparents,andtherearedifferentcases:

    Bothparentscarriers:25%childaffected Justoneparentcarrier:nochildaffected,50%willbecarrier

    Oneparentcarrier,otheraffected:allchildrencarriers,50%affected Oneparentaffected:allchildrencarriers,noaffected.

    Pathologies:Cysticfibrosisisanautosomalrecessivedisorderthatcausessevere

    lungproblemsinaffectedpersons;Sicklecellsdisease.

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    X-linkedrecessivetraits:

    MalesareXYandthereforehaveonlyonecopyoftheX-chromosome;theydont

    haveasecondXtooffsettheexpressionofamutantalleleontheaffectedX.

    Thus,similartoautosomaldominantdisorders,X-linkedrecessivedisorders

    expressthetraitfullyinmales,eventhoughnothomozygous.Femalesrarely

    showX-linkedrecessivedisordersbecausebeinghomozygousforthedisorderis

    veryrare.Inpedigrees,X-linkedrecessivedisordershavethefollowing

    characteristics:moremalesthanfemalesaffected;skiponeormoregenerations,

    traitisneverpassedfromfathertoson.

    Somepathologyinvolved:Hemophilia,Duchennemusculardystrophy,alsoX-

    linkedrecessiveconditionscansometimesmanifestinfemalesduetoskewedX-

    inactivationormonosomyX(Turnersyndrome).

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    X-linkedDominanttraits:

    Likeautosomaldominantdisorders,X-linkeddominanttraitsdontskipgen-

    erations.Everypersoninheritingthealleleexpressesthedisorder.Affectedmothershavebothaffectedsonsanddaughters;alldaughtersofaffectedfathers

    areaffected.

    Diseases:SomeX-linkeddominantconditions,suchasRettsyndrome,

    incontinentiapigmentitype2andAicardisyndrome,areusuallyfatalinmales

    eitherinuteroorshortlyafterbirth;exceptionstothisfindingareextremelyrare

    casesinwhichboyswithKlinefeltersyndrome(47,XXY)alsoinheritanX-linked

    dominantconditionandexhibitsymptomsmoresimilartothoseofafemalein

    termsofdiseaseseverity.

    Y-linkedDominanttraits:theY-chromosomeispassedstrictlyfromfatherto

    son.Bydefinition,Y-chromosometraitsareconsideredhemizygous,meaning

    theresonlyonecopyofthechromosome,nottwo.Doesnotskipgenerations.

    Examplesaremaleinfertilityandhypertrichosispinnae.