7/31/2019 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.