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GeneticBasisofDiseases
assan re s e . .
epartmento oc em stry
FacultyofMedicine
Internationa Universityo A rica,K artoum,Su an
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DISORDERS
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SINGLEGENEDISORDERS
AUTOSOMAL CODOMINANAT DISORDERS
Familialhypercholesterolemia.
.
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FHisanautosomalcodominant disorder
Causedbyalargenumber(>900)ofmutationsinthe
LDL rece tor ene on chromosome 19.
arac er ze ye eva e p asma eve so
withnormaltriglycerides,tendonxanthomas,and
.
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Isaveryrareautosomalcodominant disorder
CausedbymutationsinthegeneencodingABCA1.
ABCA1isacellulartransporterthatfacilitateseffluxof
unes er e c o es ero an p osp o p s romce s
toapoAI
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.
Thediseaseischaracterizedby:
1. Cholesterolaccumulationinthe
reticuloendothelial system2. He atos lenome al
3. Enlarged,yellowororangetonsils.
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TANGIERDISEASE
Thecholesterolefflux
necessaryforthetransferof
freecholesterol(FC)and
phospholipid (PL)outofcells.
Itbelongstothefamilyof
ATPbindingcassettetransporter
Source:James
Scott
Nature
400,
816
819(26
August
1999)
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CODOMINANCE
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XlinkedDisorders
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SINGLEGENEDISORDERS
SEXLINKED
XLINKEDDISORDERS
Severecombinedimmunodeficienc .
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SegregationofanXlinkedrecessiveallelewhen
themother
is
acarrier
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SegregationofanXlinkedrecessiveallelewhen
thefather
is
affected
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traitcharacterizedbydecreasedabilitytoperceivecolor
differences.
deficiencies:monochromacy,dichromacy, andanomalous
trichromacy.
Man ofthe enesinvolvedincolorvisionareontheX
chromosome,makingcolorblindnessmorecommonin
malesthaninfemales.
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DMD anX n e recess vemuscu ar ystrop y
associatedwithmutationsinthedystrophin geneinthe.
Dystrophin isanimportantstructuralproteinwithinmuscletissue.
DMDischaracterizedbyrapidmuscledegenerationleadingtolossinambulation,respiratoryfailureand
death.
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Summaryofmechanismsinvolvedinthecausation
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DUCHENNE MUSCULARDYSTROPHY(DMD)
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haemophilia A,haemophilia BandvonWillebrand disease.
Symptoms
Thesymptomsofhaemophilia aremainly:1. Prolon edbleedin fromin uries.
2. Frequentorheavynosebleeds.
3. Tracesofbloodintheurine.4. Heavymenstrualbleedinginfemales.
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Haemophilia A isthemostcommon(80%ofcases)
bleedingdisorderaffecting 1in5000males.ItisanX
linkedrecessive disorderduetodeficiencyof
coagulationfactorVIII.
locatedontheXchromosomeatXq28withpoint
.
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Haemophilia B islesscommon(20%ofcases)than
inheritance,andisduetomutationsinthefactorIX
.
u a ons n sgeneareusua ypo n mu a onsor
smalldeletionsorduplications.
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Haemophilia Cisanautosomaldisorder(notXlinked)due
tolackoffunctionalclottingFactorXI.
ThegeneforfactorXIislocatedonchromosome4anditis
notcompletelyrecessive,i.e.individualswhoare
heterozygousalsoshowincreasedbleeding(doeseffect)
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.
Itiscause y e iciencyo vonWi e ran actor
requiredforplateletadhesion
TherearethreetypesofhereditaryvWD,TypeI,IIand
III.
WithinthethreeinheritedtypesofvWD thereare
various subt es.
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vonWillebrand
inheritedinanautosomal
dominant pattern.
TypeIIIisinheritedas
autosoma recess ve.
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Xlinkeddominantdisorders
disorderthataffectsbothhemizygous malesand
heterozygousfemales.
(vitaminDresistantrickets)andoculomotor
nystagmus.
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Xlinkeddominantdisorders
Thegeneistransmittedthroughfamiliesinthe
samewayasXlinkedrecessivegenes:females
theirdaughters;malestransmitthemutationtoall
theirdaughtersandnoneoftheirsons.
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ArecausedbymutationsingenesontheXchromosome.
OnlyafewXlinkeddominantdisordershavebeen
recognized.
Malesaremorefre uentl affectedthanfemales
menandwomen.
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notbeaffected,andhisdaughterswillallinheritthe
condition.
chanceofhavinganaffecteddaughterorsonwitheachpregnancy.
SomeXlinkeddominantconditions suchasAicardisyndrome,arefataltoboys,andonlyseeningirlsandboys
withKlinefelter syndrome.
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XSCID alsocalledAlymphocytosis,orGlanzmannRiniker
syndrome.
Itisasevereheritableimmunodeficiencyduetoadefectin
oneofseveralpossiblegenes.
MostcasesofXSCID areduetomutationsinthegene
encodingthecommongammachain(c),aproteinthatissharedbythereceptorsforseveralinterleukinsleadingto
completefailureoftheimmunesystem.
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ThesecondmostcommonformofSCIDafterXSCIDis
causedbythedeficiencyofadenosinedeaminase (ADA),w c ca a o ze pur nes.
SCIDisanautosomal
recessive
metabolicdisorder.
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SummaryofprobableeventsinthecausationofSCIDdueto
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LackofADAcausesaccumulationofdATP whichinhibits
theactivityofribonucleotide reductase.
Ribonucleotide reductasegeneratesdRNT requiredfor
lymphocyteproliferation.
LackofdRNT inhibitslymphocyteproliferationand
compromisetheimmunesystem.
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Aicardi Syndromeisararegeneticmalformation
syndromecausedbyadefectontheXchromosome.
Characterizedbythepartialorcompleteabsenceof
thecorpuscallosum.
Aicardi syndromehasonlybeenobservedingirlsorin
' .
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YlinkedDisorders
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SINGLEGENEDISORDERS
SEXLINKED
YLIKEDDISORDERS
MaleInfertilit .
Hypertrichosis pinnae (Excesshairontheear).
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n e sor ersarecause ymu a onson e
chromosome.
InYlinkedinheritance,onlymaleswouldbeaffected.
TransmissionisfromafathertoallsonsviatheY
chromosome
ThemaingeneinYchromosomeistheSRYgene,which
.
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Hypertrichosis pinnae
Excessivehairontheearpinna
Ylinkedgeneticdisorder
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disorders
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Genetic isor ersmaya so ecomp ex,mu ti actoria or
polygenic,thismeansthattheyarelikelyassociatedwiththe
effectsofmultiplegenesincombinationwithlifestyleand
environmenta actors.
Multifactoral disordersincludeheartdiseaseanddiabetes,
goutandtheyoftenclusterinfamilies.
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multiplegenes,oftencoupledwithenvironmental
.
2. HYPOTHYROIDISM
3. COLONCANCER
4. BREASTCANCERANDOVARIANCANCER5. ALZHEIMER'SDISEASE
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GOUT HYPERURICEMIA
Goutisagenetic/acquireddisorderofuricacidmetabolism
thatleadstohyperuricemia.
arthritis.
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GOUT HYPERURICEMIA
Theoccurrenceof outis artl enetic contributin to
about60%ofvariabilityinuricacidlevel.
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Themostcommoninheritedformofhypothyroidismis
adefectoftheTPO(thyroidperoxidase)geneon
c romosome .
Thisgeneplaysanimportantroleinthyroidhormone
production.
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TheBRCA1andBRCA2genesarecalledtumor
suppressorgenesbecausetheyprevent
uncon ro e ce grow .
BRCA1islocatedonchromosome17,andBRCA2
islocatedonchromosome13.
ScientistsbelieveBRCA1andBRCA2workby
fixingdamagedorbrokenDNA.
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WomenwhoinheritamutatedcopyoftheBRCA1or
chromosomes,andthereforehaveagreaterchanceof
accumulatingmutationsthatwillleadtouncontrolled
ce grow an cancer.
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'
Alzheimer'sisadiseasethatcausesdementia,orlossof
brainfunction.
Itaffectsthepartsofthebrainthatdealwithmemory,
thought,andlanguage.
Mutationsingenesfoundonchromosomes1,14,and21
arelinkedtorarerformsofthedisease,whichstrike
earlierinlife.
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MitochondrialInheritance
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. .
2. Has37genescodefor13proteins,ribosomalRNAand
transferRNA.
3. Thegeneticcodeisdifferentfromtheuniversalcode.
.
mutantmitochondrialgenes.
MITOCHONDRIALDNA:
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Thistypeofinheritance,alsoknownasmaternal
inheritance,appliestogenesinmitochondrialDNA.
Becauseonlyeggcellscontributemitochondriatothe
developingembryo,onlyfemalescanpasson
mitochondrialconditionstotheirchildren.
AnexampleofmitochondrialdisorderistheLeber's
HereditaryOpticNeuropathy(LHON)
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'
LHONisusuallyduetooneofthreepathogenic
mitochondrialDNA(mtDNA)pointmutations.
Thesemutationsaffectnucleotidepositions11778,3460
and14484,respectivelyintheND4,ND1andND6
subunitgenesofcomplexIoftheoxidative
p osp ory at on c a n nm toc on r a.
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'
LHONischaracterizedbydegenerationofretinalganglion
cells and their axons which leads to an acute or subacutelossofcentralvision
Itaffectspredominantlyyoungadultmales.
Leber'sHereditaryOptic
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y p
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Reference
1. Helen
M
Kingston,
ABC
OF
CLINICAL
GENETICS,
Thirdedition2002,London