Molecular Genetics

Molecular genetics made simple

1. PREPARED BY : IRSA IKHLAQ
SESSION : 2019-23
DEPARTMENT OF ZOOLOGY, GC SIALKOT

2. TOPIC :
MOLECULAR GENETICS MADE SIMPLE

3. •THE STRUCTURE OF DNA AND ITS PACKING
The First Piece of the Puzzle: Miescher Discovers DNA
DNA was first identified in the late 1860s by Swiss chemist Friedrich Miescher. Then,
in the decades following Miescher’s discovery, other scientist notably, Phoebus
Levene and Erwin Chargaff--carried out a series of research efforts that revealed
additional details about the DNA molecule.
Due to its occurrence in the cells’ nuclei, he termed the novel substance “nuclein”—a
term still preserved in today’s name deoxyribonucleic acid.

4. •LAYING THE GROUNDWORK
Levene Investigates the Structure of DNA
Levene proposed that nucleic acids were composed of a series of nucleotides, and that
each nucleotide was in turn composed of just one of four nitrogen-containing bases, a
sugar molecule, and a phosphate group.
Chargaff’s rule:
The amount of adenine (A) is usually similar to the amount of thymine (T), and the
amount of guanine (G) usually approximates the amount of cytosine (C). In other
words, the total amount of purines (A + G) and the total amount of pyrimidines (C +
T) are usually nearly equal.

5. •LEVENE’S STRUCTURE OF DNA &CHARGAFF”S RULE

6. •WATSON AND CRICK’S DERIVATION
RosalindFranklinandMauriceWilkins
contributedtoWatsonandCrick’s
derivationofthethree-dimensional,
double-helicalmodelforthestructureof
DNA.
DNAisinfactcomposedofaseriesof
nucleotidesandthateachnucleotidehas
threecomponents:aphosphategroup;
oradeoxyribose(inthecaseofDNA)
sugar;asinglenitrogen-containingbase.

7. •DNA PACKAGING: NUCLEOSOMES AND
CHROMATIN
Thehaploidhumangenomecontainsapproximately3billionbasepairs
ofDNApackagedinto23chromosomes,mostcellsinthebody(exceptforfemale
ovaandmalesperm)arediploid,with23pairsofchromosomes.Thatmakesatotalof
6billionbasepairsofDNApercell.Becauseeachbasepairisaround0.34
nanometerslong,eachdiploidcellthereforecontainsabout2metersofDNA[(0.34×
10
-9
)×(6×10
9
)].itisestimatedthatthehumanbodycontainsabout50trillioncells—
whichworksoutto100trillionmetersofDNAperhuman.
DNA,Histones,andChromatin:
ProteinscompactchromosomalDNAintothemicroscopicspaceoftheeukaryotic
nucleus.Theseproteinsarecalledhistones,andtheresultingDNA-proteincomplexis
calledchromatin.

8. •CHROMOSOMES ARE COMPOSED OF DNA
TIGHTLY-WOUND AROUND HISTONES

9. •THE NUCLEOSOME: THE UNIT OF CHROMATIN
Thebasicrepeatingstructural(andfunctional)unitofchromatinisthenucleosome,which
containseighthistoneproteinsandabout146basepairsofDNA.
ChromatinIsCoiledintoHigher-OrderStructures:
ThepackagingofDNAintonucleosomesshortensthefiberlengthaboutsevenfold.In
otherwords,apieceofDNAthatis1meterlongwillbecomea"string-of-beads"
chromatinfiberjust14centimeters(about6inches)long.chromatinisfurthercoiled
intoanevenshorter,thickerfiber,termedthe"30-nanometerfiber,"becauseitis
approximately30nanometersindiameter.
ChromosomesAreMostCompactedDuringMetaphase:
Duringthedifferentphasesofthecellcycle,theDNAvariesintheextentofits
condensation.Forexample,duringinterphasethechromatinfibresare
organizedintolongloops,whereasinmetaphasechromosomes,theDNAis
compactedtoabout1/10,000ofitsstretchedoutlength

10. •TRANSCRIPTION
Transcriptionisthefirststageoftheexpressionofgenesintoproteins.In
transcription,anmRNA(messengerRNA)intermediateistranscribedfromoneofthe
strandsoftheDNAmolecule.
TheRNAiscalledmessengerRNAbecauseitcarriesthe"message,"orgenetic
information,fromtheDNAtotheribosomes,wheretheinformationisusedtomake
proteins.
RNAandDNAusecomplementarycodingwherebasepairsmatchup,similartohow
thestrandsofDNAbindtoformadoublehelix.

11. •TRANSCRIPTION

12. •DIFFERENCES IN TRANSCRIPTION
Therearesignificantdifferencesintheprocessoftranscriptioninprokaryotesversus
eukaryotes.Inprokaryotes(bacteria),transcriptionoccursinthecytoplasm.Ineukaryotes,
transcriptionoccursinthecell'snucleus.mRNAthenmovestothecytoplasmfortranslation.
DNAinprokaryotesismuchmoreaccessibletoRNApolymerasethanDNAineukaryotes.
EukaryoticDNAiswrappedaroundproteinscalledhistonestoformstructurescalled
nucleosomes.EukaryoticDNAispackedtoformchromatin.WhileRNApolymeraseinteracts
directlywithprokaryoticDNA,otherproteinsmediatetheinteractionbetweenRNA
polymeraseandDNAineukaryotes.
mRNAproducedasaresultoftranscriptionisnotmodifiedinprokaryoticcells.Eukaryotic
cellsmodifymRNAbyRNAsplicing,5'endcapping,andadditionofapolyAtail.

13. •STEPS OF TRANSCRIPTION
Transcriptioncanbebrokenintofivestages:
pre-initiation,initiation,promoterclearance,
elongation,andtermination.
Pre-Initiation:
Thefirststepoftranscriptioniscalledpre-
initiation.RNApolymeraseandcofactors
(generaltranscriptionfactors)bindtoDNAand
unwindit,creatinganinitiationbubble.It's
similarinappearancetowhatyougetwhenyou
unwindstrandsofmulti-plyyarn.Thisspace
grantsRNApolymeraseaccesstoasingle
strandoftheDNAmolecule.Approximately14
basepairsareexposedatatime.

14. •INITIATION
TheinitiationoftranscriptioninbacteriabeginswiththebindingofRNApolymeraseto
thepromoterinDNA.Transcriptioninitiationismorecomplexineukaryotes,wherea
groupofproteinscalledtranscriptionfactorsmediatesthebindingofRNApolymerase
andtheinitiationoftranscription.
Elongation:
OnestrandofDNAservesasthetemplateforRNAsynthesis,butmultipleroundsof
transcriptionmayoccursothatmanycopiesofagenecanbeproduced.
PromoterClearance
Thenextstepoftranscriptioniscalledpromoterclearanceorpromoterescape.RNA
polymerasemustclearthepromoteroncethefirstbondhasbeensynthesized.The
promoterisaDNAsequencethatsignalswhichDNAstrandistranscribedandthe
directiontranscriptionproceeds

15. •STEPS OF TRANSCRIPTION
Initiation: Elongation:

16. •TERMINATION
Terminationisthefinalstepoftranscription.
Terminationresultsinthereleaseofthenewly
synthesizedmRNAfromtheelongationcomplex.In
eukaryotes,theterminationoftranscriptioninvolves
cleavageofthetranscript,followedbyaprocess
calledpolyadenylation.Inpolyadenylation,aseries
ofadenineresiduesorpoly(A)tailisaddedtothe
new3'endofthemessengerRNAstrand.
pre-RNAandmRNA:
Aftertranscription,eukaryoticpre-mRNAsmust
undergoseveralprocessingstepsbeforetheycanbe
translated

17. •PROCESSING OF MRNA
Thethreemostimportantstepsofpre-mRNAprocessingaretheadditionofstabilizingandsignaling
factorsatthe5′and3′endsofthemolecule,andtheremovalofinterveningsequencesthatdonot
specifytheappropriateaminoacids.
5′Capping:
Acapisaddedtothe5′endofthegrowingtranscriptbyaphosphatelinkage.Thisadditionprotectsthe
mRNAfromdegradation.Inaddition,factorsinvolvedinproteinsynthesisrecognizethecaptohelp
initiatetranslationbyribosomes.
3′Poly-ATail:
Onceelongationiscomplete,anenzymecalledpoly-Apolymeraseaddsastringofapproximately200A
residue,calledthepoly-A(50–250adeninemoleculesanda70kDaprotein)tailtothepre-mRNA.
Thismodificationfurtherprotectsthepre-mRNAfromdegradationandsignalstheexportofthecellular
factorsthatthetranscriptneedstothecytoplasm.

18. •ALTERNATIVE SPLICING
Alternativesplicingisamolecularmechanismthatmodifiespre-mRNAconstructs
priortotranslation.ThisprocesscanproduceadiversityofmRNAsfromasingle
genebyarrangingcodingsequences(exons)fromrecentlysplicedRNAtranscripts
intodifferentcombinations.
Mechanismsofalternativesplicing:
PriortoRNAsplicing,RNApolymeraseIIproducespre-mRNAtranscriptsby
transcribinggenesequencesintoacollectionofnon-codingintronsandprotein-
codingexons.Whenthesepre-mRNAsequencesundergoconstitutivesplicing,the
removalofintronsisfollowedbythejoiningofexonsintheirDNA-corresponding
order

19. MECHANISMS OF ALTERNATIVE SPLICING

20. •TYPES OF SPLICING
Exonskipping:Thisprocessinvolvestheremovalof
certainexonsandtheiradjacentintronsfrommRNA
constructspriortotranslation.
Alternate5’or3’splicing:Alternativesplicingcan
alsobemediatedbythejoiningofexonsatalternative
5’or3’splicesites.
Intronretention:Thistypehappenswhennon-
codingportionsofageneareretainedinthefinal
mRNAtranscript.
Importanceofsplicing:
Themechanismsofalternativesplicinghelpto
explainhowonegenecanbeencodedintonumerous
proteinswithvariousfunctions.

21. •TRANSLATION
TranslationistheprocessofconvertingmRNAintoanaminoacidchain.DNAstoresthe
informationforproteinsinitsnucleotidesequence.ThematuremRNAmoleculescanbe
translatedtoproteins.
Thisprocesstakesplaceinthecytoplasmwiththeaidofribosomeswhichareeither
floatinginthecytoplasmorchillingonthesurfaceoftheroughendoplasmicreticulum,
whicharecomplexesofRNAsandproteinscalledribonucleoproteins.
Theribosomesaredividedintotwosubunits:thesmallersubunitbindstothemRNA,
whilethelargersubunitbindstothetRNAwhichcarriestheaminoacids.
ThetranslationprocessendswiththestopcodonsUAA,UGAorUAG.Thenascent
polypeptidechainisthenreleasedfromtheribosomeasamatureprotein.Insomecases,
thenewpolypeptidechainrequiresadditionalprocessingtomakeamatureprotein

22. •STEPS OF TRANSLATION
1)Initiation:
Duringinitiationthesmallsubunitattachestothe5'endofmRNA.Itthenmovesinthe5'→3'direction.
ThesmallsubunitthenreadsthemRNAnucleotidesingroupsofthree,calledcodons,untilitrunsinto
thestartcodonwhichisalwaysAUG
.2)Elongation:
Intheelongationphaseoftranslation,thetRNAwiththecorrectcorrespondinganticodonwillmatch
withthecorrespondingmRNAcodon.Apeptidebond,whichisthetypeofbondthatholdsaminoacids
together,Theribosomethenshiftsdownmovinginthe5'→3'direction,makingspaceforanothertRNA
tomatchwithitscorrespondingcodonandtherebyallowinganotherpeptidebondto
form.Elongationalwaysgoesfromthe5'endofthemRNAmoleculetowardsthe3'end.
3)Termination:
Thefinalphaseoftranslationistermination.Whentheribosomereachesastopcodon(UAG,
UAA,orUGA),areleasefactorwillbindtothestopcodonandcausetheaminoacidchainto
bereleasedandtheribosomebreaksofffromthemRNAstrandandtheribosomesubunitsto
separate.

23. •STEPS OF TRANSLATION (PROTEIN SYNTHESIS)

24. •GENETIC VARIATION
Geneticvariationreferstogeneticdifferencebetweenindividualswithinorbetweendifferentpopulations.
Thesevariationscanbedividedinpolymorphismsandmutations.
Polymorphism:
Polymorphismsaredefinedasvariantsfoundin>1%ofthegeneralpopulation.Duetotheirhigh
frequencytheyareconsideredunlikelytobecausativeofgeneticdisease.Theycanhowever,together
withothergeneticandenvironmentalfactors,affectdiseasepredisposition,diseaseprogressionor
responsetotreatments.
Mutation:
Mutationscanbeinheritedfromparents(germlinemutations)oracquiredoverthelifeofanindividual
(somaticmutations),thelatterbeingtheprincipaldriverofhumandiseaseslikecancer.
Germlinemutationsoccurinthegametes.MutationsusuallyarisefromunrepairedDNAdamage,
replicationerrors,ormobilegeneticelements.

25. •TYPES OF POLYMORPHISMS
Threecommontypesofpolymorphismsarethe
1.singlenucleotidepolymorphisms(SNPs)
2.smallinsertions/deletions(indels)
3.large-scalecopynumberpolymorphisms(CNPsorCNVs).
Singlenucleotidepolymorphisms:
SNPsaresinglebasechangesthatoccuronaverageaboutevery1000basesinthegenome.
MostSNPsareneutral;yet3–5%arethoughttohaveafunctionalrole,i.e.affectthephenotype
oftheindividualcarryingthem.Dependingontheireffectattheproteinlevel.
SNPscanbecharacterizedassynonymous(codingforthesameaminoacidasthewildtype
DNAsequence)ornon-synonymous(codingforadifferentaminoacidthanthewildtypeDNA
sequence).

26. •SINGLE-NUCLEOTIDE POLYMORPHISMS
(SNPS)

27. •TYPES OF POLYMORPHISMS
Smallinsertions/deletions(indels):
Indelsaresmallinsertionsordeletionsrangingfrom1to10,000bpinlength,although
themajorityinvolvesonlyafewnucleotides.
Theyareconsideredthesecondmostcommonformofvariationinthehumangenome
followingSNPs,withover3millionshortindelslistedinpublicdatabases.
Large-scalecopynumberpolymorphisms(CNPsorCNVs).
CNVsarevariationsinthenumberofcopiesofDNAregions.Theycaninvolvelossof
oneorbothcopiesofaregionofDNA,orthepresenceofmorethantwocopiesofthis
region.TheycanarisefromDNAdeletions,amplifications,inversionsorinsertionsand
theirsizecanrangefrom1kb(1,000bases)toseveralmegabases

28. •COPY NUMBER VARIATIONS

29. •TYPES OF MUTATIONS
Pointmutations:
Pointmutationsinwhichasinglenucleotideischangedforadifferentone.
Thesearedividedinto:
Missensemutations(meaningthatwhentranslatedthisDNAsequenceleadstotheincorporationof
adifferentaminoacidintotheproducedprotein,withpossibleimplicationsintheproteinfunction),
Nonsensemutations(wherethenewnucleotidechangesthesequencesothata‘‘stop’’codonis
formedearlierthaninthenormalsequenceandthereforetheproducedproteinistruncated),
Silentmutations(wherethenucleotidechangedoesnotaffecttheaminoacidinthecorresponding
positionoftheproducedprotein,andthereforethefinalproteinproductremainsunaltered),
Splice-sitemutations(whichaffectsthesplicesiteinvariantdonororacceptordinucleotides(5’GTor
3’AG).

30. •TYPES OF MUTATIONS
Insertions:
InsertionsinwhichoneormorenucleotidesareinsertedinthenormalDNAsequence,
thereforedisruptingit.Thiscanhaveamoderateorsevereeffectonthecorresponding
mutantproteinproduct.
Deletions:
DeletionsinwhichoneormorenucleotidesaredeletedfromthenormalDNA
sequence.Asinthecaseofinsertionsthiscanleadtominor(e.g.singleaminoacid
changes)ormajorproteindefects.

31. •TYPES OF MUTATIONS
Amplifications
Amplificationsleadingtomultiplecopiesofchromosomalregionsandconsequentlytoanincreasednumberofcopies
ofthegeneslocatedwithinthemandincreasedlevelsofthecorrespondingproteins.
Inversions
InversionsinvolvingthereversaloftheorientationofaDNAsegment,withvariableimplicationsfortheprotein
product.
Translocations
Translocationswhereregionsfromnon-homologouschromosomesareLoss-of-functionmutationscanbeassociated
withhaploinsufficiency,acommonoccurrenceinthemolecularcardiomyopathysetting.
HaploinsufficiencyoccurswhenthegeneproductofoneofthetwoallelesinanindividualislostduetoaDNAdeletion
ortoinstability/degradationofthemutantprotein.Othertermsusedtodescribetheeffectofamutationonthefitnessof
thecarrierare:harmfulordeleteriousmutations(decreasesthefitnessofthecarrier),beneficialoradvantageous
mutations.

32. •TYPES OF MUTATIONS

33. •DISTINGUISHING POLYMORPHISM FROM
MUTATION IN GENES
DistinguishingPolymorphismfrommutationingenes:
Ageneissaidtobepolymorphicifmorethanonealleleoccupiesthatgene'slocuswithina
population.Inadditiontohavingmorethanonealleleataspecificlocus,eachallelemustalso
occurinthepopulationatarateofatleast1%togenerallybeconsideredpolymorphic.
Mutation”and“polymorphism”:earlierdefinition
TheuniformandunequivocaldescriptionofsequencevariantsinhumanDNAandprotein
sequences(mutations,polymorphisms)wereinitiatedbytwopaperspublishedin1993.Inthis
context,anyrarechangeinthenucleotidesequence,usuallybutnotalwayswithadisease
causingattribute,istermeda“mutation”.Thischangeinthenucleotidesequencemayormay
notcausephenotypicchanges.

34. •DIFFERENCE BETWEEN GENE
POLYMORPHISM AND MUTATIONS
Aruleofthumbthatissometimesusedistoclassifygeneticvariantsthatoccurbelow1%allele
frequencyasmutationsratherthanpolymorphisms.However,sincepolymorphismsmayoccuratlow
allelefrequency,thisisnotareliablewaytotellnewmutationsfrompolymorphisms.
Identification:
Polymorphismscanbeidentifiedinthelaboratoryusingavarietyofmethods.Manymethodsemploy
PCRtoamplifythesequenceofagene.Onceamplified,polymorphismsandmutationsinthesequence
canbedetectedbyDNAsequencing,eitherdirectlyorafterscreeningforvariationwithamethodsuch
assinglestrandconformationpolymorphismanalysis.
Geneswhichcontrolhaircolourarepolymorphic.
Genepolymorphismscanoccurinanyregionofthegenome.Themajorityofpolymorphismsaresilent,
meaningtheydonotalterthefunctionorexpressionofagene.Somepolymorphismsarevisible.For
example,indogstheElocuscanhaveanyoffivedifferentalleles,knownasE,Em,Eg,Eh,and
e.Varyingcombinationsoftheseallelescontributetothepigmentationandpatternsseenindogcoats.

35. •DISEASE DUE TO VARIANT OF A GENE
Apolymorphicvariantofagenecanleadtotheabnormalexpressionortothe
productionofanabnormalformoftheprotein;thisabnormalitymaycauseorbe
associatedwithdisease.
Forexample,apolymorphicvariantofthegeneencodingtheenzymeCYP4A11,in
whichthymidinereplacescytosineatthegene'snucleotide8590positionencodesa
CYP4A11proteinthatsubstitutesphenylalaninewithserineattheprotein'samino
acidposition434.Thisvariantproteinhasreducedenzymeactivityinmetabolizing
arachidonicacidtothebloodpressure-regulatingeicosanoid,20-
hydroxyeicosatetraenoicacid.Astudyhasshownthathumansbearingthisvariantin
oneorbothoftheirCYP4A11geneshaveanincreasedincidenceofhypertension,
ischemicstroke,andcoronaryarterydisease.

36. DISEASE DUE TO MUTATION OF GENE

37. •MODE OF INHERITANCE —CLINICAL AND GENETIC
HETEROGENEITY
Onceamutationhasbeendirectlyassociatedwithapathologicalphenotypeanumberof
additionalparametersneedtobeevaluatedinordertomaximizeitsvalueintheclinical
setting.
.Thecategorizationgonosomalorautosomaldependsonwhetherthemutationsare
locatedoneitherofthesexchromosomesornot.Forexample,amutationontheY
chromosomewillonlyaffectmales.
Inhypertrophiccardiomyopathy(HCM)anumberofcaseshavebeenreportedwith
homozygosityforthepathogenicmutation.
Forexample,inEgyptianHCMcohort,noneofthemutation-positivepatientswere
homozygousforthemutationdetected(datanotpublished)whichmightbeexplained
eitherbytherarityofitsoccurrenceinthespecificcohortorduetotechnicallimitations
inthemutationscreeningmethod.

38. •MUTATION SCREENING
Mutationscreeningbydenaturing
high performance liquid
chromatography(dHPLC)using
WAVE,Transgenomics.dHPLCcan
beusedasinitialmutationscreening
method,beingdependentonhetero
duplex(wildtype-mutant)
formation,andvariantprofilesfrom
thewildpatternaresubsequently
sequenced.
Notehowever,thatdHPLCisnot
capableofdetectinghomozygosity.

39. CONTINUED…..
Thephenomenaofvariableexpressivity(variations
inaphenotypeamongindividualscarryinga
particulargenotype)andepistasis(onegeneis
modifiedbyoneorseveralothergenes,e.g.
modifiergenes)canleadtoarangeofpathological
characteristicsdespitethepresenceofthesame
mutation.Theseparameters,potentiallyin
combinationwithenvironmentalfactors,canoften
leadtosignificantclinicalheterogeneityinmost
inheritedCVDs,betweenunrelatedindividualsas
wellasfamilymemberscarryingthesame
mutation.

40. CONTINUED….
Forexample,inHCMthepresenceofmultiplepathogenicmutationscouldbe
includedamongsttheriskstratificationcriteria.Multiplemutationshavebeen
observedinabout5%ofHCMpatientsandtheyareusuallyassociatedwithhigher
septalthicknessandworseclinicaloutcomes,suchasheartfailureandsuddendeath.
DoubleheterozygosityiscommonlydetectedintheβMyosinheavychain(MYH7)
andMyosinbindingproteinC(MyBPC)genes.
CompoundheterozygosityinMyBPChowever,leadingtotheabsenceofanormal
protein,hasbeenreportedtoresultsinneonataldeathintwoindependentcases,where
theparentswereeachheterozygousforoneofthemutations.Similarly,toHCM,
doubleheterozygosityhasbeenreportedinotherCVDssuchaslongQT,witha
similarfrequencyof5%.

41. •SIGNIFICANCE OF GENETIC TESTINGINCARDIOLOGY
Inclinicalpractise,genetictestingcanserve 3 mainpurposes:
Todeterminethemodeofinheritanceofthespecificdiseaseinthespecificfamilyandidentifyifthereisriskfor
otherfamilymembers.
ToorganisetheclinicalassessmentofunaffectedfamilymembersthroughgenetictestingToidentifyifthereisri
skforotherfamilymembers.
Predictivegenetictesting:
Toidentifythosewhoareatriskforthediseaseandshouldbetreatedregularcardiacmonitoring(mutationcarrie
rs)andthosewhodonotmutationnon-carriers.
Identificationofdistinctgenotype–phenotypecorrelations:
Geneticscreening:
Ifpatientisvaluable, then Initially,providedthegenotype–
phenotyperelationship,atthediagnostic/prognostic/therapeuticlevel associationswereformed.
Theseassociationsvarygreatlybetweenindividuals.
cardiovasculardiseases,variousgenes,andvariousmutations.
Itisimportanttonote,however,thatgenetictestinginthecardiovascularfieldisstillinitsearlystages.

42. •IMPORTANCE OFPRE-SYMPTOMATIC GENETICTESTING
Fortheproband'sfamilymembers,rangesfromensuringthatcarriersofunaffectedmutationsreceiveregular
clinicalfollow-upto
prophylactictreatment(whereavailable)toreassurethatclinically'suspicious'findingsarenotpresent.
Negative Genetic Testing:
Negativegenetictestresultintheproband'sdeath.
Familymemberscannotruleoutthepresenceofdiseaseingeneral,becausealargenumberofpeoplehaveit.
PathologicalCardiovascularPhenotype:
Bychance,afamilymembermaybeacarrier,
adistinctgenemutationAnHCMpositivefamily'spedigreefromtheBAHCMStudy.
Thesister'sHCMdiagnosiswasruledout.
However,theproband'ssymptom-freeandecho-clearson.
Attheageof12years,hetestedpositiveforthemutationandwasgivenapre-
symptomaticdiagnosisofHCM.
Symbolsinwhiterepresentunaffectedindividuals,whilethoseinblackhaveHCMbasedonclinicalorgenet
icevidence.
.

43. •GENETIC TESTING
ForlongQTsyndromeandcatecholaminergicpolymorphicventriculartachychardia,andoccasionallyin
highriskHCMfamilies,inwhichpreventivemeasuresorprophylactictherapyisadvisablefor
asymptomaticmutationpositivefamilymembers,genetictestingshouldbeundertakeninearlychildhood,
i.e.regardlessofage.
Ontheotherhand,forlate-onsetand/orreducedpenetrancediseases,itisreasonabletoproceedwith
clinicalmonitoringasneededduringchildhood,leavingthegenetictestingoptionopenforwhenthe
individualreachesadulthood
WhenachildhasalreadypresentedwithaCVD,theuseofgenetictestingiscomplementarytoallother
clinicaltests,andespeciallyvaluableforidentifyingotherfamilymembersatrisk,sincechildhood-onset
cases,evenwhenpresumedassporadic,canoftenhaveageneticaetiology.
Example:
Hypertrophyhasageneticbasisandbridgingthecardiovascularandgeneticcause.

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