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N I C H DEuniceKennedyShriverNational InstituteofChildHealthandHumanDevelopment

AutismResearchattheNICHD

U.S.DEPARTMENT OF HEALTHAND HUMAN SERVICESNational InstitutesofHealth

AutismandGenesTheEuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD),part

of

the

National

Institutes

of

Health

(NIH),

within

the

U.S.DepartmentofHealthandHumanServices,isoneofmanyfederalagenciesdoingresearchonautism,includingitspossiblecauses.In1997,theNICHDandtheNationalInstituteonDeafnessandOtherCommunicationsDisorders(NIDCD)startedtheNetworkontheNeurobiologyandGeneticsofAutism:CollaborativeProgramsofExcellenceinAutism(CPEA).ResearchersinthisNetworkworktounderstandwhichgenesmightbeinvolvedinautismandhowgenesplayaroleinthecondition. Workingwithotherscientistsaroundtheworld,theCPEAresearchershavealreadylearnedagreatdealaboutautismandgenes.Whataregenes?GenesarepiecesofDNA,materialthatcontainsalltheinformationneededtobuildaperson. Genesarehereditary,meaningparentspassgenesontotheirchildren.Mostgeneticmaterialisfoundinthenucleusofacell,astorageareathatkeepsthesematerialstogetherinoneplace. Thenucleusstoresgeneticmaterialsinpackagescalledchromosomes. Mostpeoplehave46chromosomesinmostoftheircells: 23fromtheirmotherand23fromtheirfather. Eachchromosomeismadeupofgenes.Genescontaintheinformationyourbodyusestomakeproteins,thebodysbuildingblocks. Proteinsmakeupthestructureofyourorgansandtissues;theyarealsoneededforthebodyschemicalfunctionsandpathways. Eachproteinperformsaspecificjobinthebodysdifferenttypesofcells,andtheinformationformakingatleastoneproteiniscontainedinasinglegene.

ChecktheGlossaryonpages9 11 to

learnhow

to

saytheboldedwordsandwhat

theymean.

www.nichd.nih.gov
http:///reader/full/www.nichd.nih.govhttp:///reader/full/www.nichd.nih.gov


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AUTISMRESEARCH AT THENICHD

Thepatternorsequenceofyourgenesislikeablueprintthattellsyourbodyhowtobuilditsdifferentparts. Forexample,yourgenescontrolhowtallyouare,whatcoloryoureyesandhairare,andotherfeaturesofyourbodyandmind.Changes,ormutationsintheblueprintcanchangehowthebodyormindgrows/develops.Whatisautism?Autismisacomplexneurobiologicaldisorderofdevelopmentthatlaststhroughoutapersonslife.Itissometimescalledadevelopmentaldisabilitybecauseitusuallystartsbeforeagethree,inthedevelopmentalperiod,andbecauseitcausesdelaysorproblemsinmanydifferentskillsthatarisefrominfancytoadulthood.Themainsignsandsymptomsofautisminvolve1language,socialbehavior,andbehaviorsconcerningobjectsandroutines:Communicationbothverbal(spoken)and

non verbal (unspoken,suchaspointing,eyecontact,orsmiling)

Socialinteractionssuchassharingemotions,understandinghowothersthinkandfeel(sometimescalledempathy),andholdingaconversation,aswellastheamountoftimeapersonspendsinteractingwithothers

Routinesorrepetitivebehaviorsoftencalledstereotypedbehaviors,suchasrepeating

wordsoractionsoverandover,obsessivelyfollowingroutinesorschedules,playingwithtoysorobjectsinrepetitiveandsometimesinappropriateways,orhavingveryspecificandinflexiblewaysofarrangingitems

Peoplewithautismmighthaveproblemstalkingwithyou,ortheymightnotwanttolookyouintheeyewhenyoutalktothem. Theymayhavetolineuptheirpencilsbeforetheycanpayattention,ortheymaysaythesamesentenceagainandagaintocalmthemselvesdown. Theymayflaptheirarmstotellyoutheyarehappy,ortheymighthurtthemselvestotellyoutheyarenot. Somepeoplewithautismneverlearnhowtotalk.Thesebehaviorsnotonlymakelifedifficultforpeoplewhohaveautism,butalsotakeatollontheirfamilies,theirhealthcareproviders,theirteachers,andanyonewhocomesincontactwiththem.Becausedifferentpeoplewithautismcanhaveverydifferentfeaturesorsymptoms,healthcareprovidersthinkofautismasaspectrumdisorderagroupofdisorderswitharangeofsimilar

features.

Based

on

their

specific

strengths

andweaknesses,peoplewithautismspectrumdisorders(ASDs)mayhavemildsymptomsormoreserioussymptoms,buttheyallhaveanASD. ThisfactsheetusesthetermsASDandautismtomeanthesamething.Whatcausesautism?Scientistsdontknowexactlywhatcausesautism.Muchevidencesupportstheideathatgeneticfactorsthatis,genes,theirfunction,andtheirinteractionsareoneofthemainunderlyingcausesofASDs. But,researchersarentlookingforjustonegene. Currentevidencesuggeststhatasmanyas12ormoregenesondifferentchromosomesmaybeinvolvedinautismtodifferentdegrees.

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AUTISMANDGENES

Somegenesmayplaceapersonatgreaterriskforautism,calledsusceptibility. Othergenesmaycausespecificsymptomsordeterminehowseverethosesymptomsare. Or,geneswithmutationsmightaddtothesymptomsofautismbecausethegenesorgeneproductsarent

workingproperly.Researchhasalsoshownthatenvironmentalfactors,suchasviruses,mayalsoplayaroleinautism.

Whilesomeresearchersareexamininggenesandenvironmentalfactors,otherresearchersarelookingatpossibleneurological,infectious,metabolic,andimmunologicfactorsthatmaybeinvolvedinautism.Becausethedisorderissocomplex,andbecausenotwopeoplewithautismareexactlyalike,autismisprobablytheresultofmanycauses.Whystudygenestolearnaboutautism?Pastresearchlinksautismandgenes. Forexample: StudiesoftwinswithautismScientistshave

studiedautisminbothidenticaltwinswhoaregeneticallythesameandfraternaltwinswhoaregeneticallysimilar,butnotthesame. Whenidenticaltwinshaveautism,bothhaveautismmorethan60percent1ofthetime,dependingonthecriteriaused.

Whenfraternaltwinshaveautism,bothhaveautismbetween0percent2and6percentofthetime. Ifgeneswerenotinvolvedinautism,therateofautismwouldbethesameforbothtypesoftwins.

FamilystudiesofautismStudiesoffamilyhistoriesshowthatthechancesabrotherorsisterofsomeonewhohasautismwillalsohaveautismisbetween2percentand8percent3,whichismuchhigherthaninthegeneralpopulation. Also,someoftheautism like symptoms,suchasdelaysinlanguagedevelopment,occurmoreoften4inparentsandadultbrothersandsistersofpeoplewithautismthaninfamilieswhohavenomembersorrelativeswithASDs. Becausemembersofthesamefamilyaremorelikelytosharegenes,somethingaboutthesegenessequencesappearstoberelatedtoautism.

DiagnosabledisordersandautismInabout5percent5ofautismcases,anothersingle gene disorder,chromosomedisorder,ordevelopmentaldisorderisalsopresent.Thistypeofco occurrence helpsresearchers

whoaretryingtopinpointthegenesinvolvedinautism. Similardisordersorconditions

withsimilarsymptomsmayhavesimilargeneticbeginnings. Incasesofonedisordercommonlyoccurringwithanother,itcouldbethatoneisactuallyariskfactorfortheother.Thiskindofinformationcanprovidecluesto

whatactuallyhappensinautism. Forexample,manypeoplewithASDsalsohaveepilepsy, aconditionmarkedbyseizures. Ifscientistscanunderstandwhathappensinepilepsy,theymayalsofindcluestowhathappensinautism.

Basedontheseandotherfindings,scientistshavelongfeltthattherewasalikelylinkbetweengenesandautism.

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But,howsymptomsofASDsaffectfamilymembersandthewidevarietyofsymptomsin

ASDstellresearchersthattheyarentlookingforjustonegene. So,evenwhenscientistsfindthegenesinvolvedinautism,theirworkwillbejustbeginning. Theywillstillhavetouncoverwhatrolesthegenesplayinthecondition.Howdoresearcherslookforthegenesinvolvedinautism?Scientistsgenerallyuseacombinationofmethodstofindcandidategenesgeneslikelytobeinvolvedinautism.

Screenthewholegenome.AgenomeisallthegeneticmaterialinapersonscellstheirDNA,theirgenes,andtheirchromosomes. Usually,researchersscreenthegenome

of

afamily

or

aset

of

families

that

has

morethanonememberwithanASD,tolookforcommonfeaturesanddifferences. Theylookforso called linksbetweenthosediagnosedwith

ASDsandthegeneswithinthesefamilies. Usingmarkerlocationsgeneswhosepositioninthegenomeisknownresearchers cannarrowdownthelocationofgenesinvolvedinASD. Ifageneinvolvedwithautismisclosetoaparticularmarker,scientistscanidentifythisgenebymappingitinrelationtotheknownmarkers.Conductcytogeneticstudies.Inacytogeneticstudy,researchersstainchromosomeswithadyeandthenlookatthemunderamicroscope. Thedyecreateslightanddarkbandsthatareuniquetoeachchromosome.Researcherscomparetheresultingbandsoftwo

peoplewithautism,ofonepersonwithautismandonerelative,orofonepersonwithautismandonepersonnotaffectedbyASD. Thesecomparisonscanpointoutsimilaritiesanddifferencesbetweenregionsonthechromosome,

whichresearcherscanthenstudyfurtherbasedonthetraitsofthatspecificregion.

Examinelinkageratios.Researchersusethisapproachtotofindhotspotsareasonchromosomesthatmaycontaingenesinvolvedinautism. Hotspotsarelikeneighborhoodsonthechromosome

wherethegenesinvolvedinautismmightreside. Inmanycases,genesinthesameareaofachromosomearetightlyconnectedtooneanother,andthisconnectionishardtobreak. Iftheconnectionispresentinmorepeoplethanyoumightexpectbychance,thesituationiscalledlinkagedisequilibrium.Linkagedisequilibriumhelpsresearchersnarrowtheirgeneticsearchtofindthespotinthechromosomalneighborhoodwherethegenemightbe.

Evaluategenesbasedontheirknownfunctions.Insomecases,researchersalreadyknowwhatthenormalfunctionofaspecificgeneorgenesis. Ifthatspecificfunctionisabnormalorincompleteinautism,researcherscanlookatthegenescontrollingthatfunctioninapersonwithautismtoseewhatisdifferentormissing. Or,theycanlookatwhatkindsofmedicationsareusefulincorrectingorcontrollingthatfunctiontoreducethesymptomsofautism. Theycanthenstudythechemicalpathwaysthatthesemedicationseffecttoseewhatstepmightbechangedor

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AUTISMANDGENES

missinginautism. Oncetheyvefoundthepathwayorthechange,theycanlookatthegenesthatcontrolthesefeaturesformoreinformationaboutautism. Thisapproachisknownasgeneticassociationanalysis.Whathaveresearchersfoundbystudyinggenesandautism?ResearchersintheCPEANetworkandtheircolleaguesaroundtheworldhavelearnedalotaboutautismthroughgeneticstudies,buttheystillhaveagreatdealtolearn. Todate,someoftheirfindingsincludethefollowing.

ChromosomeswhereimportantgenesarelikelytobefoundUsing genome wide screens, scientists have

identifiedanumberofgenesthatmightbeinvolvedinautism. Althoughsomeanalysessuggestthatasmanyas12genes6mightbeinvolvedinASDs,thestrongestevidence7,13pointstoareason: Chromosome2Scientistsknow7,10,11,12that

areasofchromosome2aretheneighborhoodsforhomeoboxorHOXgenes,thegroupofgenesthatcontrolgrowthanddevelopmentveryearlyinlife. Youhave38differentHOXgenesinyourchromosomalneighborhoods,andeachonedirectstheactionofothergenesinbuildingyourbodyandbodysystems.ExpressionoftheseHOXgenesiscriticaltobuildingthebrainstemandthecerebellum,twoareasofthebrainwherefunctionsaredisruptedinASDs.

Chromosome7Researchershavefound6,7,8,9averystronglinkbetweenthischromosomeandautism. TheirinvestigationsnowfocusonaregioncalledAUTS1,whichisverylikelyassociatedwithautism. MostofthegenomestudiescompletedtodatehavefoundthatAUTS1playssomeroleinautism. Thereisevidencethataregionofchromosome7isalsorelatedtospeechandlanguagedisorders.BecauseASDsaffectthesefunctions,autismmayinvolvethischromosome.

Chromosome13Inonestudy,35percent7,9offamiliestestedshowedlinkageforchromosome13. Researchersarenowtryingtoreplicatethesefindingswithotherpopulationsoffamiliesaffectedbyautism.

Chromosome15Genome wide screensandcytogeneticstudiesshowthatapartofthischromosomemayplayaroleinautism.Geneticerrorsonthischromosomecause

AngelmansyndromeandPrader Willi syndrome,bothofwhichsharebehavioralsymptomswithautism.Cytogeneticerrorsonchromosome15occur9inupto4percentofpatientswithautism.

Chromosome16Genesfoundonthischromosomecontrolawidevarietyoffunctions7that,ifdisrupted,causeproblemsthataresimilarorrelatedtosymptomsofautism. Forexample,ageneticerroronthischromosomecausestuberoussclerosis, adisorderthatsharesmanysymptomswithautism,includingseizures. So,regionsonthischromosomemayberesponsibleforcertainsimilarbehavioralaspectsofthetwodisorders.

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Chromosome 17A recent study found the

strongest evidence13 of linkage on this

chromosome among a set of more than 500

families whose male members were diagnosed

with autism. Missing or disrupted genes on

this chromosome can cause problems, such as

galactosemia, a metabolic disorder that, if left

untreated, can result in mental retardation.

Chromosome 17 also contains the gene for

the serotonin transporter, which allows nerve

cells to collect serotonin. Serotonin is

involved in emotions and helps nerve cellscommunicate. Problems with the serotonin

transporter can cause obsessive-compulsive

disorder (OCD), which is marked by

recurrent, unwanted thoughts (obsessions)

and/or repetitive behaviors (compulsions).

The X chromosomeTwo disorders that share

symptoms with autismFragile X syndrome

and Rett syndromeare typically caused by

genes on the X chromosome, which suggeststhat genes on the X chromosome may also play

a role in ASDs. People generally have 46

chromosomes in most of their cells23 from

their mother and 23 from their father. After

fertilization, the two sets match up to form 23

pairs of chromosomes. The chromosomes in

the 23rd pair are called the sex chromosomes,

X and Y. Their combination determines a

persons sexmales usually have one X and

one Y chromosome, and females usually havetwo X chromosomes. The fact that more

males than females have autism supports5,9 the

idea that the disorder involves genes on the X

chromosome. Females may be able to use their

other X chromosome to function normally,

while males, without such a back up show

symptoms of the condition.

Potential candidate genes

By focusing their studies on hot spots,

researchers have narrowed their search for

candidate genes. They need to do more work

to understand how many genes are involved,

and how these genes interact with each other

and with the environment to cause autism.

Researchers do have some promising leads

more leads than can be mentioned in this fact

sheet, but these are a few.

Researchers have found evidence that autism may

involve the HOXA1 gene. HOXA1, a homeobox

gene, plays a critical role in the development of

important brain structures, cranial nerves, the

ear, and the skeleton of the head and neck.

Researchers know that the HOXA1 gene is active

very early in lifebetween the 20th and 24th

days after conceptionand that any problem

with the genes function causes problems with the

development of these structures. Such problems

may contribute to the features of autism.

In one study10, nearly 40 percent of the persons

with autism carried a specific mutation in the

HOXA1 gene sequencenearly twice as many as

those who had the same change, but who did not

have autism and were not related to anyone with

autism. In addition, 33 percent of those who did

not have autism but were related to someone

with autism also had the mutation in their

HOXA1 gene. These findings mean that autismdoes not result from genetics alone, but that

some other factors are also involved in causing

the condition. If researchers can confirm an

association between this mutation and ASDs,

they may be able to detect the mutation as an

early test for autism, allowing important

interventions to start as early in life as possible.

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AUTISM RESEARCH AT THE NICHD


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AUTISM AND GENES

Another study11 found that increased head size

in ASD patients was associated with a differentmutation in the HOXA1 gene. About 20 percent

of persons with autism have large head size. It is

one of the most consistently reported physical

features of persons with autism. Now researchers

want to know whether the mutation affects head

size in persons with autism only, or if it affects

head size in general, regardless of ASD status.

Several other genes have come forward as

potential candidates, including:

The Reelin (RELN) gene on chromosome 7

This gene plays a crucial role in the

development of connections between cells of

the nervous system. Researchers think that

abnormal brain connectivity plays a role in

autism, which makes Reelin a good candidate.

In addition, persons with autism and their

parents and siblings have lower levels of certain

types of the Reelin protein, which may meanthat gene is not functioning normally.

The HOXD1 geneThis homeobox gene is

critical to the formation of certain brain

structures. This gene is involved in Duane

syndrome, a disorder that causes eye-

movement problems and sometimes occurs

with autism. In one study12 of persons with

autism, nearly 94 percent of participants had

mutations in the same regions of HOXD1,which could mean that the region contributes

to ASDs.

Gamma-amino-butyric acid (GABA)

pathway genesGABA compounds are

neurotransmitters, which means they help

parts of the nervous system communicate with

each other. GABA receptor genes are involved

in early development of parts of the nervous

system and help with communication between

these parts throughout life. A problem in the

GABA pathway can cause some of the

symptoms of ASDs. For instance, epilepsy

may result, in part, from low levels of GABA

compounds. Many persons with autism alsohave epilepsy and also show low levels of

GABA. Current research focuses on genes

that, when their structure or function is

incorrect, cause autism-like problems in mice.

Serotonin transporter gene on chromosome 17

The serotonin transporter allows nerve

cells to collect serotonin so that they can

communicate. Serotonin is a neurotransmitter

involved in depression, alcoholism/problemdrinking, OCD, and other disorders. Research

shows that persons with autism have higher-

than-normal levels of serotoninranging

between 25 percent and 50 percent9,13 higher

than persons without autism. This higher

serotonin level may result from problems with

the serotonin transporter that arise from errors

in the gene.

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BodychemicalsthatmayplayaroleinautismThe body makes many chemicals that help it

functioncorrectly. Whenthesechemicalsaremissingorincorrect,thebodymayhaveproblemsfunctioningproperly,whichmayresultinsymptomsofautismorotherdisorders.Researchersarenowtryingtouncoverhowbodychemicalsmightbeinvolvedinautism,sotheycanlearnhowthegenesthatmakethesechemicalsmightalsoplayarole. Researchersarealsostudyingwhethermedicationsmightregulateorcontrolthesechemicalstocreatenormalchemicallevels. NormalizingthechemicalsinapersonwithASDsmightreducesymptoms.

Asmentionedearlier,GABAmayplayaroleinautismanddefinitelyplaysaroleinepilepsy.LevelsofdifferenttypesofGABAcompoundsareabnormallylowinpersonswithautism.Researchersbelievethattheselowlevelsmaycontributetoautism. Instudiesofmice,disruptingtheGABApathwaycausesseizures,extremereactionstotouchandsound,andstereotypedactionssymptomsalsocommoninautism. Researchnowfocusesonwhethermedicationsusedtotreattheseproblemscanalsoreducesomeofthesymptomsofautism.

Anotherbrainchemicalmentionedearlierserotoninisalsoout of balance inmanypersonswithautism. Highserotoninlevelsmayexplainwhypersonswithautismhaveproblemsshowingemotionandhandlingsensoryinformation,suchassounds,touch,andsmells.Researchersnowfocusonwhethermedicationsthatregulateserotoninlevelsmayimprovebehaviorinpersonswithautism. Theyalsoexaminethegenesthatmakeandregulateserotoninanditspathwaycomponentstoseeiftheycanfindanychangesorpatterns.

Whatdoesthefutureholdforstudiesofgenesandautism?ScientistsintheCPEANetworkandtheircolleagueswhostudythegeneticmechanismsofautismhopethatthesestudieswillrevealthemaincauseorcausesofautism. Doctorscouldthentestforthegeneorgenestodetectautismearlyinlifesothatinterventioncanbegin

whenitismosteffective. Or,researcherscoulddevelopdrugsthatchangeorregulatethegeneorgenestohelpnormalizebodychemicalsandbodyfunctions.Researcherssharetheirinformationandtheirmethodstoseeifotherresearcherscanreplicatetheirfindings. Havingseveralscientistsgetthesameresultsconfirmsthatdiscovery. Onceconfirmed,adiscoverybecomesthesteppingstonetootherdiscoveries. Todate,however,notallgeneticstudieshavegottenthesameresults.Therefore,additionalworkisstillimportant.Scientistsalsolookbeyondgenestofindfactorsthatmayplayaroleinautism,includingthingsintheenvironment. Environmentalfeaturescanaffecthowgenesfunction,whichmaycontributetothesymptomsofASDs. Byunderstandinggeneticandenvironmentalcausesofautism,scientistsmaybetterunderstandhowtotreatitandmaybeevenhowtopreventit. Doctorsandscientistscontinuetostudygenes,theenvironment,andgene environment interactionsuntiltheysolvethemysteriesofautism.

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AUTISMANDGENES

GlossaryTheword Ispronounced AndmeansAngelmansyndrome Ayn JELL mann

sinn DROM AgeneticdisordercausedbyabnormalfunctionofthegeneUBE3A,locatedwithinasmallregiononchromosome15. Characteristicsinclude:developmentaldelay,lackofspeechorminimaluseofwords;movementorbalancedisorder,usuallyataxiaofgaitand/ortremulousmovementoflimbs,andanycombinationoffrequentlaughter/smiling;apparenthappydemeanor;easilyexcitablepersonality,oftenwithhandflappingmovements;hypermotoricbehavior;shortattentionspan.

Candidategene kan di DATE jeen

Agene,locatedinachromosomeregionsuspectedofbeinginvolvedinadisorder,whoseproteinproductsuggeststhatitcouldbethegeneinquestion.

Chromosome kro mu SOM Oneofthe"packages"ofgenesandotherDNAinthenucleusofacell.Humanshave23chromosomepairs,46inall.Eachparentcontributesonechromosometoeachpair,sochildrengethalfoftheirchromosomesfromtheirmothersandhalffromtheirfathers.

Cytogenetic sigh TOW jenn eh tik Studyofchromosomesusingaspecificmethodthatinvolvesstainingachromosomeandexaminingitunderamicroscope.

Duanesyndrome DWAYNEsinn DROM Aninheriteddisordercharacterizedbyinabilityofoneorbotheyestoturnoutwardbeyondthemidline. Insome

casesthereisalsoadeficitofinwardmotilityoftheeye(turningtowardthenose).

Epilepsy epp ih LEPP see Abraindisorderinwhichclustersofnervecells,orneurons,inthebrainsometimessignalabnormally.Inepilepsy,thenormalpatternofneuronalactivitybecomesdisturbed,causingstrangesensations,emotions,andbehaviororsometimesconvulsions,musclespasms,andlossofconsciousness.

FragileXsyndrome FRA jell EKSsinn DROM Themostcommonformofinheritedmentalretardation.Amutationinasinglegene,theFMR1geneontheX

chromosome,causesthedisorder,whichcanbepassedfromonegenerationtothenext.Symptomsoccurbecausethemutatedgenecannotproduceenoughofaproteinthatisneededbythebodyscells,especiallycellsinthebrain,todevelopandfunctionnormally.

Fraternaltwins frah TURN ul twinns Twinsresultingfromthefertilizationoftwoseparateeggs. Fraternaltwinsshareabout50percentoftheir

genes,justlikesiblingswhoarebornatdifferenttimes.Galactosemia guh lak toe SEE mee

uh Araredisorderinwhichthebodycannotprocessthesugargalactose,aby product ofmilkmetabolism.Buildupofgalactosepoisonsthebody,causingliver,kidney,andeyedamage,andevendeath(ifuntreated).

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Glossary(Continued)The word Is pronounced And meansGene jeen PiecesofDNA. Theycontaintheinformationfor

makingaspecificprotein.Genome JEE nom AlltheDNAcontainedinanorganismoracell;includes

boththeDNAandchromosomeswithinthenucleusandtheDNAoutsidethenucleus.

Hereditary ha RED ih tarry Ageneortraitpasseddownfromparenttooffspring.Homeoboxgenes HOE mee oh boks

jeenz Genesfoundinalmostallanimalsthatcontrolhowandwherepartsofthebodydevelop. Activeveryearlyinlife,actinglikeamoviedirectorbytellingothergeneswhentoactandwhentostopinbuildingthebody.

Hotspots hot spotz Areasonchromosomeswheremutations,activity,orrecombinationoccurswithunusuallyhighfrequency.

Identicaltwins eye DEN tik ul twinns Twinsformedfromthesplittingofthesamefertilizedegg,sotheyshare100percentoftheirgeneticmaterial.

Linkagedisequilibrium LINK aj DISS ee kwel ih bree

umAnassociationofgenesand/ormarkersneareachotheronachromosomethatismorethanwouldbeexpectedbychance.Linkedgenesandmarkerstendtobeinheritedtogether.

Mutation my TAH shun ApermanentstructuralchangeinDNA.Inmostcases,DNAchangeseitherhavenoeffectorcauseharm,butsomemutationsimproveanorganismssurvival.

Neurotransmitter

nyur OH tranz mitt er

Asubstance

that

transmits

nerve

impulses

between

nervecells.

Nucleus NOO klee us Thecentralcellstructurethathouseschromosomes.Obsessive

compulsivedisorder(OCD)

ahb SESS iv kum PUL shen DISS or dr

Adisordercharacterizedbyrecurrent,unwantedthoughts(obsessions)and/orrepetitivebehaviorsoranurgentneedtoperformrituals(compulsions).

Prader Willi syndrome PRAY derr WILL ee sinn DROM Anuncommoninheriteddisordercharacterizedbymentalretardation,decreasedmuscletone,short

stature,emotionalliability,andaninsatiableappetitethatcanleadtolife threatening obesity. Causedbyamissingpartonthepaternallyderivedchromosome15.

Protein

PRO teen

Alarge

molecule

made

up

of

one

or

more

chains

of

aminoacids.Proteinsperformawidevarietyofactivitiesinthecellandinthebody.

Replicate repp li KATE Describesasituationinwhichmanystudiesthatusethesamemethodsandstepshavegottenthesameoutcome,suggestingthatafindingislikelytobetrue.

Rettsyndrome RETTsinn DROM ResultsmostlyfrommutationsintheMECP2geneontheXchromosomeandoccursalmostexclusivelyin

girls.Afterseeminglynormaldevelopment,affectedgirlsdevelopproblemswithlanguage,learning,coordination,andotherbrainfunctions.

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AUTISMANDGENES

Glossary(Continued)The word Is pronounced And meansSeizure SEE jyur Asuddenattack,oftenoneofconvulsions,asin

epilepsy. Seizuresdontnecessarilyinvolvemovementorthrashing;theycanalsomakesomeoneseemasthoughtheyarefrozen,unmoving.

Serotonin serr oh TOE ninn Aneurotransmitterthatisfoundespeciallyinthebrain,bloodserum,andstomachliningofmammals.

Stereotyped STARE ee oh tipd Anactionthatisrepeatedwithoutchange.Susceptibility suss ept ih BULL Thestateofbeingpredisposedto,sensitiveto,orof

lackingtheabilitytoresistmanifestationsofsomething(suchasapathogen,familialdisease,oradrug);apersonwhoissusceptibleismorelikelytoshowsymptomsofadisorder.

Tuberoussclerosis TOOB er us sklar OH siss Arare,multi system geneticdiseasethatcausesnon cancerous tumorstogrowinthebrainandon

othervitalorganssuchasthekidneys,heart,eyes,lungs,andskin.Itcommonlyaffectsthecentralnervoussystemandresultsinacombinationofsymptomsincludingseizures,developmentaldelay,behavioralproblems,skinabnormalities,andkidneydisease.

References1.Folstein&Rutter,1977;Bailey,etal,1995;Smalley,etal,1988,ascitedinIngram,2000.2.Steffenburg,etal,1989,ascitedinMuhle,2004.3.Gillberg,etal,2000;Chakrabarti,etal,2001;Chudley,

etal,1998,ascitedinMuhle2004.4. Landa,etal,1991;Landa,etal,1992;Volkmar,etal,

1998;MacLean,etal,1999,ascitedinIngram,2000.5.Gillberg.(1998).Chromosomaldisordersandautism.

JournalofAutismandDevelopmentalDisorders,28:415 425. 6.IMGSAC.(1998).Afullgenomescreenforautismwith

evidenceforlinkagetoaregionofchromosome7q.HumanMolecularGenetics,7:571 578

7.CollaborativeLinkageStudyofAutism(1999).Anautosomalgenomicscreenforautism.AmericanJournalofMedicalGenetics,88:609 615; andInternationalMolecularGeneticStudyofAutismConsortium(2001).

Agenomewidescreenforautism:Strongevidenceforlinkagetochromosomes2q,7q,and16p.AmericanJournalofHumanGenetics,69:570 581.

8.IMGSAC.(2001).FurthercharacterizationofautismsusceptibilitylocusAUTS1onchromosome7q.HumanMolecularGenetics,10(9):973 982.

9.Muhle,etal.(2004).TheGeneticsofAutism.Pediatrics,113(5):e472 e486.

10.IngramJL,StodgellCJ,HymanSL,FiglewiczDA,WeitkampLR,andRodierPM.(2000).DiscoveryofallelicvariantsofHOXA1andHOXB1: geneticsusceptibilitytoautismspectrumdisorders. Teratology,62:393 405.

11.Conciatori,etal.(2004).AssociationbetweentheHOXA1A218Gpolymorphismandincreasedheadcircumferenceinpatientswithautism. JournalofBiologicalPsychiatry,55:413 419.

12.Stodgell,etal.(2004).AssociationofHOXD1andGBX2allelicvariantswithautismspectrumdisorders.PresentedattheCPEA/STAARTAnnualScientificMeeting.

13.Cantor,etal.(2005).Replicationofautismlinkage:Finemappingpeakat17q21.AmericanJournalofHumanGenetics,76:1050 1056.

TheNICHDwouldliketothankFredVolkmar,M.D.,andEdCook,M.D.,fortheirassistanceonthisfactsheet.

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How can I get involved with studies of autism?

If you are interested in taking part in one of the CPEA studies, or if you want more information about

one of the CPEA sites, visit http://www.nichd.nih.gov/autism/cpea.cfm. You and your family are welcome

to take part in many different studies, but you can only take part in one genetics study at a time.

To find out what studies related to autism are currently looking for participants, go to

http://www.nichd.nih.gov/autism/research.cfm and choose the Autism clinical trials currently recruiting

patients link.

You can also visit http://www.clinicaltrials.govor call 1-800-411-1222 for more information on federally

funded studies that are seeking participants.

AUTISM RESEARCH AT THE NICHD

Where can I go for more information about genes and autism?

For more information about the CPEA Network, genetic studies, or autismresearch, contact the NICHD. The NICHD supports and conducts research ontopics related to the health of children, adults, families, and populations,including autism and developmental disabilities. The mission of the NICHD isto ensure that every person is born healthy and wanted, that women suffer no

harmful effects from the reproductive process, and that all children have thechance to fulfill their potential for a healthy and productive life, free of diseaseor disability, and to ensure the health, productivity, independence, and well-beingof all people through optimal rehabilitation. You can contact the NICHD throughthe NICHD Information Resource Centerat:

Mail: P.O. Box 3006, Rockville, MD 20847

Phone: 1-800-370-2943 (TTY: 1-888-320-6942)

Fax: 1-866-760-5947

E-mail: [email protected] (Please use AUTISM in the subject line)

Internet: http://www.nichd.nih.gov/autism

The National Library of Medicine also provides information on ASDs athttp://www.nlm.nih.gov/medlineplus/autism.html. The NIH Web site also has informationabout ASDs at http://health.nih.gov/result.asp/62.

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NIH Pub. No. 05-5590May 2005

NICHDNational Institute of Child Health& Human Development

autism genes 2005r

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