chapter_3 - Mendelianinheritance monogenicdisorders

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Unformatted text preview: Mendelianinheritance monogenicdisorders Thesimplestgeneticcharactersarethosewhosepresenceorabsencedependsonthegenotypeatasinglelocus.Such charactersarecalledMendelianandcanberecognizedbythecharacteristicpedigreepatternstheygive.Over6000 Mendeliancharactersareknowninman. Mendeliancharactersaretypifiedbydifferentlevelsofheterogeneity: locusheterogeneity:determinationofadiseaseorphenotypebymutationsatdifferentloci allelicheterogeneity:manydifferentdiseasecausingallelesatasinglelocus clinicalheterogeneity:2ormorediseasescausedbymutationsinasinglegene NonMendelian characters depend on two, three or many genetic loci, with greater or smaller contributions from environmental factors. Multifactorial inheritance is the catchall term covering this type of genetics. The genetic determination in multifactorial characters may involve a small number of loci (oligogenic) or many loci each of individuallysmalleffect(polygenic). OMIM An essential starting point for acquiring information on Mendelian characters is the OMIM (Online Mendelian InheritanceinMan)database(http://www.ncbi.nlm.nih.gov/omim/). EachOMIMentryreceivesauniquesixdigitnumber: 1:autosomalloci(entriescreatedbeforeMay15,1994) 2:autosomalloci(entriescreatedbeforeMay15,1994) 3:Xlinkedlociorphenotypes 4:Ylinkedlociorphenotypes 5:mitochondriallociorphenotypes 6:autosomalloci(entriescreatedafterMay15,1994) Inaddition,eachentrynumberisprecededbyasymbol: *:ageneofknownsequence. #:adescriptiveentry(usuallyaphenotype) +:thedescriptionofageneofknownsequenceandaphenotype. %:aconfirmedMendelianphenotypeforwhichtheunderlyingmolecularbasisisnotknown constructingapedigree Acquiringapedigreeisanessentialstepinevaluatingapresumedgeneticconditioninafamilyorinordertoanalyse theinheritancepatternofaparticulardisease.Specificsymbolsareusedtoannotatepedigrees(seeslides). Firstdegree relatives (parentoffspring and siblings) share 50% of their genetic information. As a consequence, if a geneticaberrationispresentinanindividual,theprobabilitythatafirstdegreerelativealsoisacarrierofthatsame defectis50%.Analogously,secondandthirddegreerelativesshare25%and12,5%oftheirgenes. thefivebasicMendelianinheritancepatterns Mendelianinheritancepatternsareclassifiedas: dominantandrecessive autosomalorsexlinked(XlinkedandYlinked) The more common inheritance patterns are: autosomal dominant, autosomal recessive and Xlinked recessive. X linkeddominantandYlinkedaremorerarelyencountered. Thepatternsarediscussedinfurtherdetailbelow. autosomaldominantcharacters Atraitisdominantifitismanifestintheheterozygoteandrecessiveifitisnot.Inautosomaldominantconditionsan equal number of affected males and females are usually present in a pedigree. There is vertical transmission: the conditionispresentinallgenerations.Therecurrenceriskforaffectedindividualsis50%. Keyexamplesofautosomaldominantconditionsare: autosomalrecessiveconditions As mentioned earlier, recessive conditions manifest only in individuals that carry two mutant alleles (homozygously mutantorcompoundheterozygosity).Carriersofonemutantalleleusuallydonothaveclinicallyrelevantaberrations. Therecurrenceriskforautosomalrecessiveconditionsis25%.Horizontaltransmission(presenceofthephenotypein siblings) can be seen, male and female individuals are equally at risk. A key feature of recessive conditions is consanguinityoritspreferentialoccurrenceingeneticisolates. Wellknownexamplesare: Xlinkedrecessiveinheritance Xlinked recessive conditions are caused by hemizogosity for mutations in genes on the X chromosome and usually only produce a phenotype in males. In females, the phenotype is highly variable and depends on lyonization (see hereditaryhemochromatosis mucoviscidosis inbornerrorsofmetabolism NF1 Marfansyndrome achondroplasia Huntingtondisease Steinertdisease(myotonicdystrophy) hereditarybreastandovariancancer hereditarycolorectalcancer below). In Xlinked conditions, maternal transmission is noted: affected males are related matrilineally. The recurrence risk for Xlinked recessive conditions depends on the parent carrying the mutation. Affected facthers transmitthegeneticdefecttoalltheirdaughters(carriers)andhavenoaffectedsons.Ifamotherisacarrier,onthe otherhand,sonsofhersonswillbeaffected,whileofherdaughterswillbecarrier. TypicalXlinkedrecessiveconditionsare: Xlinkeddominantconditions Xlinkeddominantconditionsbecomephenotypicallyapparentinmalesaswellasfemales.Maternaltransmissionis againanotedcharacter.Usuallymorefemalesthanmalesareaffected.Affectedmotherstransmitthegeneticdefect tosonsanddaughters.Alldaughtersofaffectedfathersareexpectedtodevelopthephenotype,whiletheirsonsare neveraffected. Xlinkeddominantconditionsaremorerare,someexamplesare: Ylinkedinheritance The Y chromosome is relatively small and only contains a limited number of genes. Ylinked conditions produce a phenotypeinhemizygotecarriers.Evidently,onlymalesareaffectedbyYlinkedconditions. complicationsandpeculiarfeaturesofMendeliancharacters Mendeliancharactersdisplayanumberofspecificfeaturesthatcancompromiseinterpretinginheritancepatternsor diagnosingageneticdisease.Thesefeaturesinclude: reducedpenetrance agerelatedpenetrance variableexpression lethalityinmalesforXlinkedconditions mosaicism(gonadalandsomatic) pseudodominanceinrecessiveconditions anticipation imprinting denovomutations Xlinkedhypophosphatemia Xlinkedchondrodysplasiapunctata hemophilia fragileXsyndrome Fabry'sdisease Eachofthesefeaturesisdiscussedinmoredetailbelow. reducedpenetrance Penetranceisdefinedastheprobabilitythatapersonthatdisplaysapathogenicgenotypewillmanifestthecharacter. By definition, a dominant condition is manifest in a heterozygous person and therefore should show 100% penetrance.Nevertheless,manydominantcharactersoccasionallyskipageneration.Indeed:100%penetranceisthe moresurprising phenomenon. Very often, the presence orabsenceofacharacter depends on the genotypeat one locus.However,aparticulargeneticbackground,aparticularlifestyleorjustchancemayresultinanindividualfailing tomanifestacharacter. agerelatedpenetrance A particularly important case of reduced penetrance is seen in lateonset diseases. Genetic diseases are not necessarily present at birth (congenital). Although the genotype is fixed at conception, some phenotypes may not manifestuntilinadultlife.Therefore,whenevaluatingapedigree,oneshouldalwaysconsiderthefactthatcertain individualshavenotdevelopedaphenotypebecausetheyaretooyoungatthetimeofassessment. variableexpression Expressionisdefinedasthepossiblephenotypicalaberrationsassociatedwithagivengenotype.Thecauseofvariable expression is the same as with nonpenetrance: allelic heterogeneity, other genes, environmental factors and pure chancecaninfluencethedevelopmentofdiseasemanifestations.Mostgeneticdiseasedoindeeddisplayavariable expressionwithoftenanotedintraandinterfamilialvariation.Anillustrationoftherelevanceofvariableexpression relatestoscreeningfor(sub)clinicalmanifestations. Strikingexamplesofvariableexpressioninclude: malelethalityinXlinkedconditions ForsomeXlinkedconditions,absenceofthenormalalleleislethalbeforebirth.Asaconsequence:affectedmalesare notbornandweseethattheconditionaffectsonlyfemales(whopassontheconditiontotheirdaughtersbuttonone of their sons). There may be a family history of miscarriages, but families are rarely big enough to prove that the numberofsonsisonlyhalfthenumberofdaughters. AclassicalexampleofmalelethalityinaXlinkedconditionisincontinentiapigmenti,aXlinkeddominantcondition. mosaicism Mosaicismisdefinedasthepresenceoftwoormoredifferentcelllinesinanindividualderivedfromasinglezygote (as opposed to chimera: an organism derived from more than one zygote). The differences that characterise the differentcelllinescanbe:pointmutations,chromosomalaberrations,... In mosaics, the phenotype depends on the tissue distribution of the genetic aberration and the tissue dependent expressionofthemutatedgene.Mosaicismcanaffectsomaticandgerminalcells.Asthespontaneousmutationrate inhumancellsisestimatedat10 /gene/cellgenerationandasourbodiescontainapproximately10 cells,therefore eachindividualisexpectedbeamosaicfornumerousgeneticaberrations. Gonadalorgerminalmosaicismisaspecialtypeofmosaicism,andinvolvesthereproductivecells.Asaconsequence, 7 13 neurofibromatosistype1 VonHippelLindausyndrome a healthy couple, without a family history for a disease, can have several children affected by the same dominant condition.Ingonadalmosaicism,therecurrenceriskisverydifficulttoestimate,asthiswilldependonthedistribution ofthegeneticdefectinthegonadalcells. pseudodominanceinrecessiveconditions Infamilieswithahighinbreedingcoefficientorinfamiliesfromgeneticallyisolatedpopulationsthecarrierfrequency forrecessiveconditionscanbeextremelyhigh.Asaresult,recessiveconditionscanoccurfrequentlyinafamilyand mightadoptadominantinheritancepattern. aniticipation Anticipation is the tendency for the severity of a condition to increase in successive generations. Anticipation is frequently seen in conditions caused by dynamic mutations, such as repeat expansions. In these conditions, the severityofthediseasemanifestationsincreasesandtheageatonsetofthesymptomsdecreaseswithanincreasing repeatexpansionlength. imprinting Some autosomal dominant conditions (affecting both sexes) manifest only when inherited from a parent of one particular sex. These parental sex effects are evidence of imprinting, a poorly understood phenomenon whereby certaingenesaresomehowmarked(imprinted)withtheirparentalorigin.Asaresult,maternalandpaternalgenomes are not functionally equivalent: a paternal or maternal allele is consistently repressed, resulting in monoallelic expression.Ifamutantalleleisimprintedandthereforerepressed,itwillnotproduceaphenotypeinoffspring(and viceversa).Duringgametogenesis,thepaternalimprintsareerasedandarereplacedbyanewsexspecificimprint. The mechanism of imprinting is unclear, but a key component appears to be DNA methylation. Several imprinted regionsinthehumangenomehavebeenidentifiedandtendtobeorganisedinclusters. PraderWilli and Angelman syndrome (phenotypical characteristics: see slides) represent an illustrative example of imprinting.WhilePraderWilliiscausedbytheabsenceofcriticalgenesonlyactiveonthepaternalchromosome15 (maternal genes imprinted), Angelman syndrome is caused by the absence of critical genes only active on the maternalchromosome15(paternalgenesimprinted).SeveralmechanismsthatcausebothAngelmanandPraderWilli havebeenidentified,suchaschromosomaldeletions,uniparentaldisomyandmutationsintheimprintingcenter. lyonization In the somatic cells of female individuals one of the two X chromsomes is inactivated, a process which is called lyonization. Lyonization constitutes a mechanism of dosage compensation, which overcomes sex differences in the expectedratioofautosomalgenedosagetoXchromosomegenedosageinmalesandfemales. Xinactivation involves modification of the chromatin structure of the X chromosome, resulting in a condensed heterochromatized structure evidenced as the Barr body in interphase nuclei. As a consequence, females are functionallyhemizygousformostXlinkedgenes. Lyonization occurs early in embryogenesis (day 1516) and results from methylation from XIST gene (X inactivation specifictranscript),whichisexpressedontheinactivatedXchromosomeonly. SkewedXinactivationcanbeatthebasisofthepresenceofphenotypicalaberrationsinfemalecarriersofXlinked recessiveconditions.Asanexample,thevariableexpressionofFabry'sdiseaseinapedigreewithanumberoffemale carriersisgiveninthecourseslides. denovomutations Many,oftendominantorXlinkedconditionsoccurinfamilieswithoutaprevioushistoryforthedisease.Anumberof thesediseasesarelethalandthereforealwaysarisefromadenovomutation,suchasthanatophoricdysplasia. New mutations can complicate pedigree interpretation: estimating the recurrence risk can therefore be extremely difficult. For instance, if a male patient is diagnosed with Duchenne muscular dystrophy (a Xlinked recessive condition)severalmechanismscanexplainthepatternofinheritance(seeslides): III.1:denovomutation:norecurrenceriskforhismother II.1: originated from a single mutant sperm: standard recurrence risk ( of her future sons, of her future daughterscanbecarrier),noriskforaffectedoffspringinhersisters II.1isagonadalmosaic:recurrenceriskforotherchildren,hersistersarenotariskforbeingcarriers I.1:gonadalmosaic:allfemalerelativesingenerationIIareatriskforbeingacarrier,theriskforthembeinga carrierisdifficulttoestimate mitochondrialinheritance The mitochondrial genome is small ~16kb and contains 13 genes which predominantly play an important role in cellularrespiration.Themitochondrialgenomelackstherepairmechanismspresentinthenucleusandistherefore highly mutable. As sperm cells do not contribute to the mitochondria of the zygote, mitochondrial diseases have a particular inheritance pattern, which is strictly matrilineal. Mitochondrial diseases affect both sexes, but are only transmittedbyaffectedmotherstooffspring. Mitochondrialdiseasespreferentiallyaffectorganswithahighoxygendemand:skeletalmuscle,heart,brainandeyes. Prominentfeaturesinthemajorityofthesediseasesarediabetesandlacticacidosis. The expression of mitochondrial diseases is affected by the distribution of the gene defect in the mitochondria. Homoplasmy is the condition in which every mitochondrial genome carries the mutation. In heteroplasmy, a mixed populationofmutantandwildtypemitochondrialDNAispresentineachcell.Heteroplasmyandthetypeofmutation can profoundly influence the phenotypical expression of a mitochondrial disease. Heteroplasmy is heritable: if a motherisheteroplasmicforamtDNAmutation,shecantransmitnormalandmutantDNAtoherchildren.Thedegree ofheteroplasmy(andthereforethediseasemanifestations)can,however,varysignificantlybetweenthemotherand herchildren. ...
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This note was uploaded on 05/28/2010 for the course WE BIBI000000 taught by Professor Johangrooten during the Spring '10 term at Ghent University.

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