CLINICALGENOMICS

MCQsFORSTUDENTS

1.A28yearoldhealthyfemalemedicalstudent,whosefatherhadbeendiagnosedwithAdultpolycystickidney
disease(ADPKD),hadultrasoundscandoneonhertwokidneys,whichsheinquisitivelyrequestedduringa
radiologypostingandwasnormal.AweeklatersheagainrequestedforanMRI,andaT2weightedbreathheld
AdetectatruncatingmutationinthePKD2genein
MRIwithoutcontrastinjectioninonebreathholdandthisrevealedmultipletinycysts(>10/kidney)inacortical
herandherotheraffectedfamilymembers.
andperihilardistribution.DNAtestingwillmostlikely:
BdetectcontiguousdeletionofPKD1/TSC2with
resultantendstagerenaldisease.
CdetectatruncatingmutationinthePKDH1gene

abnormality.EdetectatruncatingmutationinthePKD1geneonchromosome4q21inherandherfather

2.WhichofthefollowingistrueconcerningthepathogenesisofAdultpolycystickidneydisease(ADPKD)?
AADPKDischaracterizedbynumerouscystswithintherenalcalycealsystemBMutationsofPKHD1resultin
ADPKD,pancreaticcystsandhepaticbiliarydysgenesisandfibrosis.CThecystsfluidsoriginateinmorethan
98%ofnephrons,andmostlyderivedfromglomerularfiltrate.
D.defectsinthegeneproduct,polycystin1andpolycystin2,presentintheciliaoftubularepitheliacellsdisrupt
calciumsignalingthatnormallyinhibitsrenaltubulegrowth.Edefectsinthegeneproduct,fibrocystin,foundin
thekidney,liverandpancreas,appearstobeinvolvedintheregulationofcellproliferationandadhesion

3.TheprocessofDNAsynthesisnormallyavoidstransmittingerrorstosubsequentgenerationsofcells.However,
geneticabnormalitiesofDNAmismatch/repairdooccur,andincludeallofthefollowing,except:AADPKDB
hereditarynonpolyposiscoloncancer(HNPCC)CataxiatelangiectasiaDBloomsyndromeExeroderma
pigmentosum
4.Whichofthefollowingistheleastcommoncauseofendstagerenaldisease?

AAdultpolycystickidneydiseaseBDiabetesmellitusCHypertensionDTheyallcauseESRDwithaboutthe
samefrequencyEUnknownduetocurrentlackofclinicaldata

5.Whichofthefollowingisnottrueconcerningtheanatomyofthegene?

A.AgeneproductcanoccasionallyconsistofRNAthatisnottranslated.

B.ExonsrefertotheportionofgenesthatareeventuallysplicedtogethertoformmRNA.

C.IntronsrefertothespacingregionsbetweentheexonsthataresplicedoutofprecursorRNAsduring
RNAprocessing

D.GenetranscriptionoccurswhenRNApolymerasebeginstosynthesizeRNAfromtheDNAtemplate.

E.Mutationsoccuronlyincertaindomainsofageneandpointmutationsthatintroduceaprematurestop
codonresultinanaminoacidsubstitutionifthecodonisaltered.
6.A25yearsold,otherwisehealthymale,hasbeenselectedasapotentialkidneydonor.The55yearsold
fatherhasa10yearshistoryofADPKDwithESRD.Priortothekidneytransplant,ageneticcounseling
anddirectmutationanalysisformoleculardiagnosisofADPKDinthe25yearsoldkidneydonorwas
scheduledtobeperformed.WhichofthefollowingfactsaboutDNAsequencingistrueexcept:

A.Itiscompletelyanautomatedprocedure,withtheadvantageofusingabloodsamplefromthedonor.
B.ThecapillaryelectrophoresisbasedSangermethodinwhichdideoxynucleotidesareusedtorandomlyterminate
DNApolymerizationateachofthefourbases(A,G,T,C)iscurrentlythemostcommonlyusedstrategy.
C.Theuseoffluorescentlylabeleddideoxynucleotidesallowsdetectionofthedifferentbasesanddirect
computeranalysisoftheDNAsequence.
D.NewerDNAsequencingtechnologies,suchaspyrosequencingchemistries;wholegenomesequencingusing
solidphasesequencing;massspectrometryandDNAchipsarelaboriouslesscosteffective
E.ThemajorlimitationofdirectDNAtestingisthatdefinitivediseaseassociatedmutationdarefoundinonly
about4060%ofcase.

7.Allthefollowinginformationconcerningtheanatomyoflocus,allelesandagene,aretrue,except:
A.Theparticularallelewhichcausesthecharacteristicofanindividualtobeexpressedinanormalfashionis
oftenreferredtoasthewildtypeallele.
B.IfamaleinheritsarecessivemutantallelesuchascolorblindnessonhisXchromosome,heexpresses
colorblindnessbecausehepossessesthewildtypealleleonhisYchromosome.
C.Therearetwochromosomesofeachkindandhencetwoallelesofeachkindofgene,exceptforthesex
chromosomes,whichissaidtobehemizygousforallelescarriedonthemalesXchromosome.
D.Analleleisanyoneoftwoormorealternativeformsofagenethatoccupiesafixedpositioninthe
chromosome.
E. A locus is the specific position of a particular gene or one of its alleles, in all homologous
chromosomes.

8.TechnicaladvancesinDNAsequencingandcomputationalbioinformaticshaveledtothecompletionofthe
DNAsequenceforthehumanchromosomes.WhichofthefollowingistrueconcerningtheHumanGenome
Project(HGP)anditscurrentdevelopments?

A.Thewholegenomesofotherorganismsareyettobesequencedcompletely.
B.HGPisyettocommencecomparativegenomics.
C.StudiesoflargescaleexpressionofRNAs(functionalgenomics)andproteins(proteomics)candetect
differencesbetweenvarioustissuesinhealthanddisease.
D.EfforttoexamineethicalandlegalimplicationsoftheHGPhasnotyetbeeninitiated.
E.HGPisyettoidentifygenesthatplaycriticalrolesinthedevelopmentofpolygenicandmultifactorial
disorders.

9.WhichofthefollowingstatementsareNOTTRUEconcerningmutationsandthetransmissionofgenetic
diseases:
A.ItisachangeintheprimarynucleotidesequenceofDNAregardlessofitsfunctionalconsequencesand
canoccurinthegermline(spermoroocytes)duringembryogenesisorinsomatictissues.
B.Somaticmutationsareassociatedwithneoplasiabecausetheyconferagrowthadvantagetocells.
C.Epigeneticeventsareheritablechangesthatdonotinvolvechangesingenesequence(e.g.,alteredDNA
methylation),therefore,donotinfluencegeneexpressionorgeneticdamage.
D.Mutationsareusuallystable,withtheexceptionoftripletnucleotiderepeats.
E.Ifapurineisreplacedbyanotherpurinebase(A G),thesubstitutioniscalledatransitions;ontheother
handifapurineisreplacedbypyrimidineitisreferredtoastransversions.

10.Anewlyweddedcouplecomesintoyourclinicaftertheirhoneymoonandstatesthattheyareplanningtohave
achildsoon.Themanis60yearsoldandthewomanis34yearsold.Themangaveafamilyhistoryof
achondrodysplasia,whilethewomangaveafamilyhistoryofneurofibromatosis.Theywerebothconcerned
abouttheriskoftransmittinganygeneticdiseasetotheirchildandcameinforgeneticcounselingandyour
mostlikelyresponsewouldincludeallofthefollowingEXCEPT:
A.Mutationratesaredifficulttodetermineinhumansbecausemanymutationsaresilentandbecause
testingisoftennotadequatetodetectthephenotypicconsequences.
B.Theprobabilityofacquiringnewpointmutationsismuchgreaterinthefemalegermlinethanthemale
germline,inwhichratesofaneuploidyareincreased.
C.Theincidenceofachondrodysplasia,Marfansyndromeandneurofibromatosisasaresultofnewpoint
mutationsinspermatogoniaincreaseswithpaternalage
D.Itisestimatedthatabout1in10spermcarriesanewdeleteriousmutation.
E.TheratesfornewmutationsarecalculatedforautosomaldominantandXlinkeddisordersandare~105
106/locuspergenerationandthereforenewmutationcanbetransmittedtotheaffectedindividualbutdoes
notnecessarilyimplythattheparentsareatrisktotransmitthediseasetootherchildren.

MATCHING:PARTA
A. PraderWilli syndrome (neonatal hypotonia, developmental delay, obesity, short stature, and
hypogonadism)
B.Marfansyndrome
C.Huntingtondisease
D.Singlenucleotidepolymorphisms(SNPs)
E.ADPKDcausedbyPKD2genemutation
F.FragileXsyndrome
G.Promyelocyticleukemia.

Regulationofgeneexpressionisinfluencedbyepigeneticevents,suchasgeneticimprinting,whichisa
processesinwhichDNAmethylationorhistonemodificationsisassociatedwithgenesilencing.

Thisclassofmutationconsistsofdeletionsorinsertionsthatshiftthereadingframeofthemessage

ThisclassofmutationconsistsoftrinucleotiderepeatsrepeatsthatencodesFMR1protein.

Thet(15;17)chromosomaltranslocationfusesthePMLgenetoaportionoftheretinoicacidreceptor
(RAR)gene.

AnautosomaldominantdisordercausedbyexpansionofaCAGtrinucleotiderepeatthatencodesa
polyglutaminetract.

Characterization,usingDNAchips,providesimportanttoolforcomprehensiveanalysesofgeneticvariation,
whichmaybeusefulpharmacogenomicsandpredictionofdiseasepredilection.

AngiotensinIIreceptorblockersmayslowdiseaseprogression,asdemonstratedbythehumangenomeProject.

MATCHING:PARTB

A.Frameshiftmutation
B.Missensemutation
C.synonymouspolymorphism
D.pointmutations
E.Geneconversion
F.nonsynonymouspolymorphism
G.Nonsensemutation
H.Gainoffunctionmutations
I.Inactivatingmutations
J.Haploinsufficiency

1. Mutationsinvolvingsinglenucleotides
2. DNAsequencechangethatoccursinacodingregionandtherebyaltersanaminoacidsequence
3. DNAsequencevariationsthatdonotresultinaperceptiblephenotypeandconsistofsinglebasepair
substitutionsthatdonotaltertheproteincodingsequencebecauseofthedegeneratenatureofthegeneticcode
4. Smallnucleotidedeletionsorinsertionsthatcauseashiftofthecodonreadingframe
5. SequencevariationsthataltermRNAstability,translation,oraminoacidsequence,butdonotresultina
perceptiblephenotype.
6. Readingframealterationsthatresultinanabnormalproteinsegmentofvariablelengthbeforeterminationof
translationoccursatastopcodon
7. Nonreciprocalexchangeofhomologousgeneticinformation,usedtoexplainhowaninternalportionofagene
isreplacedbyahomologoussegmentcopiedfromanotheralleleorlocus.
8. Mutationinasinglealleleinandwhichonenormalalleleisnotcapableofmaintaininganormalphenotype,
seeninVonHippelLindausyndromeandotherdiseasesassociatedwithmutationsintranscriptionfactors.
9. Mutationistypicallydominant,andresultsinphenotypicalterationswhenasinglealleleisaffected.
10. Mutationistypicallyrecessive,andtheaffectedindividualiseitherhomozygousorcompoundheterozygous
forthediseasecausingmutations.

ANSWERS
#1,ANSWER=A:
AdetectatruncatingmutationinthePKD2geneinherandherotheraffectedfamilymembers.Bdetect
contiguousdeletionofPKD1/TSC2withresultantendstagerenaldisease:thisisseenintuberoussclerosis.
CdetectatruncatingmutationinthePKDH1geneonchromosome6p21inherandherfather:thisisseen
inARPKD.DdetectatruncatingmutationintheMCKD1geneonchromosome1q21,asthecauseofher
abnormality:thisisseeninmedullarycystickidneydisease.EdetectatruncatingmutationinthePKD1
geneonchromosome4q21inherandherfather:amutationinthePKD1geneisseenonchromosome16p.

2.WhichofthefollowingistrueconcerningthepathogenesisofAdultpolycystickidneydisease
(ADPKD)?
ANSWER=D
AADPKDischaracterizedbynumerouscystswithintherenalcalycealsystem.INCORRECT:ADPKDis
characterizedbycystswithintherenalparenchyma.BothADPKDandARPKDlackcystswithintherenal
calycealsystem.BMutationsofPKHD1resultinADPKD,pancreaticcystsandhepaticbiliarydysgenesis
andfibrosis.INCORRECT:MutationsofPKHD1resultinARPKD,pancreaticcystsandhepaticbiliary
dysgenesisandfibrosis.CThecystsfluidsoriginateinmorethan98%ofnephrons,andmostlyderived
fromglomerularfiltrate.INCORRECT:Thecystsfluidsoriginateinabout2%ofnephrons,andinitially
derivedfromglomerularfiltrate,butmostlyderivedfromtransepitheliamovement.

D.CORRECT:defectsinthegeneproduct,polycystin1andpolycystin2,presentintheciliaoftubular
epitheliacellsdisruptcalciumsignalingthatnormallyinhibitsrenaltubulegrowth.Edefectsinthegene
product,fibrocystin,foundinthekidney,liverandpancreas,appearstobeinvolvedintheregulationofcell
proliferationandadhesion.INCORRECT:defectsinthegeneproduct,fibrocystin,foundinthekidney,
liverandpancreas,appearstobeinvolvedintheregulationofcellproliferationandadhesioninARPKD.

3.TheprocessofDNAsynthesisnormallyavoidstransmittingerrorstosubsequentgenerationsofcells.
However,geneticabnormalitiesofDNAmismatch/repairdooccur,andincludeallofthefollowing,except:
ANSWER:A
AADPKDBhereditarynonpolyposiscoloncancer(HNPCC)CataxiatelangiectasiaDBloomsyndromeE
xerodermapigmentosum

4.Whichofthefollowingistheleastcommoncauseofendstagerenaldisease?
ANSWER:A
AAdultpolycystickidneydiseaseBDiabetesmellitusCHypertensionDTheyallcauseESRDwithabout
thesamefrequencyEUnknownduetocurrentlackofclinicaldata
5.Whichofthefollowingisnottrueconcerningtheanatomyofthegene?
ANSWER:E.Mutationsoccurinalldomainsofageneandpointmutationsthatintroduceapremature
stopcodonresultnoaminoacidformation.

A.AgeneproductcanoccasionallyconsistofRNAthatisnottranslated.

B.ExonsrefertotheportionofgenesthatareeventuallysplicedtogethertoformmRNA.

C.IntronsrefertothespacingregionsbetweentheexonsthataresplicedoutofprecursorRNAs
duringRNAprocessing

D.GenetranscriptionoccurswhenRNApolymerasebeginstosynthesizeRNAfromtheDNA
template.

E.Mutationsoccuronlyincertaindomainsofageneandpointmutationsthatintroducea
prematurestopcodonresultinanaminoacidsubstitutionifthecodonisaltered.

6.ThefollowingfactsaboutDNAsequencingistrueexcept:
ANSWER:DNewerDNAsequencingtechnologies,suchaspyrosequencingchemistries;wholegenome
sequencingusingsolidphasesequencing;massspectrometryandDNAchipsarefasterandmorecost
effective.
A.Itiscompletelyanautomatedprocedure.
B.ThecapillaryelectrophoresisbasedSangermethodinwhichdideoxynucleotidesareusedtorandomly
terminateDNApolymerizationateachofthefourbases(A,G,T,C)iscurrentlythemostcommonlyused
strategy.
C.Theuseoffluorescentlylabeleddideoxynucleotidesallowsdetectionofthedifferentbasesanddirect
computeranalysisoftheDNAsequence.
D.NewerDNAsequencingtechnologies,suchaspyrosequencingchemistries;wholegenomesequencing
usingsolidphasesequencing;massspectrometryandDNAchipsarelaboriouslesscosteffective
E.ItispossibletodeducetheDNAsequencebyexaminingtheprogressionoffragmentlengthsgeneratedin
eachofthefournucleotidereactions,afterseparatingthearrayofterminatedDNAfragmentsusinghigh
resolutiongelorcapillaryelectrophoresis.

7.Allthefollowinginformationconcerningtheanatomyoflocus,allelesandagene,aretrue,except:
ANSWER=B
A.Theparticularallelewhichcausesthecharacteristicofanindividualtobeexpressedinanormal
fashionisoftenreferredtoasthewildtypeallele.
B.IfamaleinheritsarecessivemutantallelesuchascolorblindnessonhisXchromosome,heexpresses
colorblindnessbecausehepossessesthewildtypealleleonhisYchromosome:Ifamaleinheritsarecessive
mutantallelesuchascolorblindnessonhisXchromosome,heexpressescolorblindnessbecausehelacks
thewildtypealleleonhisYchromosome.
C.Therearetwochromosomesofeachkindandhencetwoallelesofeachkindofgene,exceptforthesex
chromosomes,whichissaidtobehemizygousforallelescarriedonthemalesXchromosome.
D.Analleleisanyoneoftwoormorealternativeformsofagenethatoccupiesafixedpositioninthe
chromosome.
E.Alocusisthespecificpositionofaparticulargeneoroneofitsalleles,inallhomologous
chromosomes.

8. TechnicaladvancesinDNAsequencingandcomputationalbioinformaticshaveledtothecompletionof
theDNAsequenceforthehumanchromosomes.WhichofthefollowingistrueconcerningtheHuman
GenomeProject(HGP)anditscurrentdevelopments?

ANSWER=C

A.Inadditiontothehumangenome,thewholegenomesofsomeorganismshavebeensequenced
partiallyorcompletely.
B.Therehavebeenadvancementsincomparativegenomics
C.TherehavebeenadvancementsinstudyoflargescaleexpressionofRNAs(functionalgenomics)and
proteins(proteomics)inordertodetectdifferencesbetweenvarioustissuesinhealthanddisease.
D.EfforttoexamineethicalandlegalimplicationsoftheHGPhavebeeninitiated
E.HGPhashelpedintheidentificationofgenesthatplaycriticalrolesinthedevelopmentofpolygenicand
multifactorialdisorders.

9.WhichofthefollowingstatementsareNOTTRUEconcerningmutationsandthe
transmissionofgeneticdiseases:
ANSWER:C

A.ItisachangeintheprimarynucleotidesequenceofDNAregardlessofitsfunctional
consequencesandcanoccurinthegermline(spermoroocytes)duringembryogenesisorin
somatictissues.
B.Somaticmutationsareassociatedwithneoplasiabecausetheyconferagrowthadvantage
tocells.
C.Epigeneticeventsareheritablechangesthatdonotinvolvechangesingenesequence(e.g.,altered
DNAmethylation),therefore,donotinfluencegeneexpressionorgeneticdamage:
ANSWER:C
Epigeneticeventsareheritablechangesthatdonotinvolvechangesingenesequence(e.g.,
alteredDNAmethylation),anditmayinfluencegeneexpressionorgeneticdamage.

D.Mutationsareusuallystable,withtheexceptionoftripletnucleotiderepeats.
Ifapurineisreplacedbyanotherpurinebase(A G),thesubstitutioniscalledatransitions;ontheother
handifapurineisreplacedbypyrimidineitisreferredtoastransversion

10.Anewlyweddedcouplecomeintoyourclinicaftertheirhoneymoonandstatesthattheyareplanningto
haveachildsoon.Themanis60yearsoldandthewomanis34yearsold.Themangaveafamilyhistoryof
achondrodysplasia,whilethewomangaveafamilyhistoryofneurofibromatosis.Theywerebothconcerned
abouttheriskoftransmittinganygeneticdiseasetotheirchildandcameinforgeneticcounselingandyour
mostlikelyresponsewouldincludeallofthefollowingEXCEPT:
ANSWER:B
A.Mutationratesaredifficulttodetermineinhumansbecausemanymutationsaresilentandbecause
testingisoftennotadequatetodetectthephenotypicconsequences.
B.Theprobabilityofacquiringnewpointmutationsismuchgreaterinthefemalegermlinethanthemale
germline,inwhichratesofaneuploidyareincreased:ANSWERB:Theprobabilityofacquiringnewpoint
mutationsismuchgreaterinthemalegermlinethanthefemalegermline,inwhichratesofaneuploidyare
increased.
C.Theincidenceofachondrodysplasia,Marfansyndromeandneurofibromatosisasaresultofnewpoint
mutationsinspermatogoniaincreaseswithpaternalage
D.Itisestimatedthatabout1in10spermcarriesanewdeleteriousmutation.
E.TheratesfornewmutationsarecalculatedforautosomaldominantandXlinkeddisordersandare~10
5106/locuspergenerationandthereforenewmutationcanbetransmittedtotheaffectedindividualbut
doesnotnecessarilyimplythattheparentsareatrisktotransmitthediseasetootherchildren.

MATCHING:PARTA_ANSWERS
A. PraderWilli syndrome (neonatal hypotonia, developmental delay, obesity, short stature, and
hypogonadism)
B.Marfansyndrome

C.Huntingtondisease
D.Singlenucleotidepolymorphisms(SNPs)
E.ADPKDcausedbyPKD2genemutation
F.FragileXsyndrome
G.Promyelocyticleukemia.

A.Regulationofgeneexpressionisinfluencedbyepigeneticevents,suchasgeneticimprinting,whichis
aprocessesinwhichDNAmethylationorhistonemodificationsisassociatedwithgenesilencing.

E.Thisclassofmutationconsistsofdeletionsorinsertionsthatshiftthereadingframeofthemessage

F.ThisclassofmutationconsistsofCGGtrinucleotiderepeatsthatencodesFMR1protein.

G.Thet(15;17)chromosomaltranslocationfusesthePMLgenetoaportionoftheretinoicacidreceptor
(RAR)gene..

C.AnautosomaldominantdisordercausedbyexpansionofaCAGtrinucleotiderepeatthatencodesa
polyglutaminetract.

D.Characterization,usingDNAchips,providesimportanttoolforcomprehensiveanalysesofgenetic
variation,whichmaybeusefulpharmacogenomicsandpredictionofdiseasepredilection.

B.AngiotensinIIreceptorblockersmayslowdiseaseprogression,asdemonstratedbythehuman
genomeProject.

MATCHING:PARTB_ANSWERS

A.Frameshiftmutation
B.Missensemutation

C.synonymouspolymorphism

D.pointmutations
E.Geneconversion
F.nonsynonymouspolymorphism

G.Nonsensemutation
H.Gainoffunctionmutations
I.Inactivatingmutations
J.Haploinsufficiency

D.Mutationsinvolvingsinglenucleotides

B.DNAsequencechangethatoccursinacodingregionandtherebyaltersanaminoacidsequence

3
C.DNAsequencevariationsthatdonotresultinaperceptiblephenotypeandconsistofsinglebase
pairsubstitutionsthatdonotaltertheproteincodingsequencebecauseofthedegeneratenatureofthe
geneticcode
4

A.Smallnucleotidedeletionsorinsertionsthatcauseashiftofthecodonreadingframe

5
F.SequencevariationsthataltermRNAstability,translation,oraminoacidsequence,butdonot
resultinaperceptiblephenotype.
6
G.Readingframealterationsthatresultinanabnormalproteinsegmentofvariablelengthbefore
terminationoftranslationoccursatastopcodon
7
E.nonreciprocalexchangeofhomologousgeneticinformation,usedtoexplainhowaninternal
portionofageneisreplacedbyahomologoussegmentcopiedfromanotheralleleorlocus.
8
J.Mutationinasinglealleleandinwhichonenormalalleleisnotcapableofmaintaininganormal
phenotype,seeninVonHippelLindausyndromeandotherdiseasesassociatedwithmutationsin
transcriptionfactors.
1. H.Mutationistypicallydominant,andresultsinphenotypicalterationswhenasinglealleleisaffected.
2. I.Mutationistypicallyrecessive,andtheaffectedindividualiseitherhomozygousorcompound
heterozygousforthediseasecausingmutations.