síndrome de x frágil -javier aram arciniega_grupo e

8/21/2019 Sndrome de X Frgil -Javier Aram Arciniega_grupo E

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FMR1-Related Disorders

Includes: Fragile X Syndrome, Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS),FMR1-

Related Primary !arian Insu""iciency (PI)

Ro#ert A Saul, $%, FA&$' and ac & Tarleton, P*%, FA&$'+

Aut*or In"ormation

Initial Posting: une , ..0 1ast Re!ision: A2ril 3, 343+

Diagnosis

Clinical Diagnosis

Fragile X syndrome.A de"inite diagnosis o" "ragile X syndrome re5uires t*e 2resence o" a loss-o"-"unction mutationinFMR1, usually in a male 6it* moderate intellectual disa#ility or a "emale

6it* mild intellectual disa#ility+

7ote: 8ecauseFMR1mutations are com2lex alterations in!ol!ing non-classicgene-disru2ting

alterations (trinucleotide re2eatex2ansion) and a#normal gene met*ylation,a""ectedindi!iduals

occasionally *a!e an aty2ical 2resentation 6it* an I9 a#o!e 4, t*e traditional demarcation

denoting intellectual disa#ility+

A""ected indi!iduals *a!e normal gro6t* and stature and no associated mal"ormations+

Fragile X-associated tremor/ataxia syndrome (FXTAS)(see Ta#le )

A defnite diagnosis o FXTASrequires the presence of a premutation inFMR1and white matter lesions on MRI in the middle cerebellar pedunclesand/or brain stem (the major neuroradiologic sign) with either intentiontremor or gait ataxia (the two major clinical signs).

Other minor neuroradiologic criteria include MRI white matter lesions in thecerebral white matter or moderate to generalied atroph!.

Other minor clinical criteria include par"insonism# moderate to se$erewor"ing memor! de%cits# or executi$e cogniti$e function de%cits.

A probable diagnosis o FXTASrequires either one major neuroradiologicsign and one minor clinical sign or two major clinical signs.

A possible diagnosis o FXTASis based on one minor neuroradiologic signand one major clinical sign &'rigsb! et al *+.

Ta#le + FXTAS: $a;or and $inor %iagnostic &riteria
http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.fxtas_major_and_minor_diagnos/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.fxtas_major_and_minor_diagnos/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/NBK1384/


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Neuroradiologic Signs Clinical Signs

Majo

r

, -remutation in FMR1and white matter lesions onMRI in the middle cerebellar peduncles and/or brainstem

, Intention tremor, 'ait ataxia

Min

or

, MRI white matter lesions in the cerebral whitematter, Moderate to generalied atroph!

, -ar"insonism, Moderate to se$erewor"ing memor! de%cits, xecuti$e cogniti$efunction de%cits

FMR1-related primary ovarian insuiciency (!"#).FMR1-related PI is de"ined as cessation

o" menses #e"ore age 8ret*eric et al 344=,

8odega et al 344? 6ere not su22orted #y a recent more ro#ust study >8ennett et al 344?+

Testing

$%romosome analysis.&*romosome analysis using modi"ied culture tec*ni5ues to induce

"ragile sites is no longer used "or diagnosis o" "ragile X syndrome #ecause it is less sensiti!e and

more costly t*an molecular genetic testing(see $olecular 'enetic Testing)+

!rotein testing.Alt*oug* 2rotein testing is not 2er"ormed routinely in most clinical la#oratory

settings, a "e6 la#oratories 2ro!ide assays t*at 5ualitati!ely measure t*e 2roduction o" t*e

2rotein 2roduct o"FMR1, "ragile X mental retardation 2rotein (F$RP) >@illemsen et al ..?+

Situations in 6*ic* F$RP testing may #e use"ul include screeningo" males 6it* intellectual

disa#ility and c*aracteriation o" cellular 2roduction o" F$RP in males *a!ing unusual

2*enoty2es+ 8ecause se!erity o" t*e "ragile X syndrome2*enoty2ea22ears to correlate 6it*

F$RP ex2ression in 2eri2*eral #lood lym2*ocytes, assessment o" F$RP 2roduction in some

a""ectedmales *as #een 2ro2osed as a 2otential 2rognostic indicator o" disease se!erity >Tassone

et al ...?+

Molecular Genetic Testing

&ene.FMR1is t*e only genein 6*ic*mutationis no6n to causeFMR1-related disorders+

Allele si'es.FMR1alleles are categoried according to t*e num#er o" &'' trinucleotide re2eats

in exon and t*e met*ylationstatus o" t*e re2eat region+ Bo6e!er, t*e distinction #et6een allelecategories is not a#solute and must #e made #y considering #ot* "amily *istoryand re2eat

insta#ility+ T*e #oundary #et6een intermediate and 2remutation categories listed #elo6 is not

2recise and caution is ad!ised+ SeeTa#le


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Normal alleles.pproximatel! *011 repeats

o lleles of this sie ha$e no meiotic or mitotic instabilit! and aretransmitted without an! increase or decrease in repeat number.

o 2he population distribution of FMR1repeat alleles shows the highestpercentage of indi$iduals with approximatel! 3045 repeats andsmaller but signi%cant percentages clustering around and 1repeats.

Intermediate alleles also termed !gra" #one! or $borderline%&.pproximatel! 1*0*1 repeats

o Intermediate alleles do not cause fragile 6 s!ndrome. 7owe$er# about518 of intermediate alleles are unstable and ma! expand into thepremutation range when transmitted b! the mother &9olin et al 55+.

2he! are not "nown to expand to full mutations: therefore# o;spring

are not at increased ris" for fragile 6 s!ndrome.

o 7istoricall!# the largest repeat included in the intermediate range hasbeen *1: the use of *1 as the upper limit for normal alleles is aconser$ati$e estimate re


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transmission.

9oteA 2he upper limit of the premutation range is sometimes noted asapproximatel! 4. Coth numbers ( and 4) are estimates deri$edfrom Bouthern blotanal!sis# in which repeat sie can onl! be roughl!estimated.

Full(mutationalleles.More than @'' repeats# with se$eral hundred tose$eral thousand repeats being t!pical and associated with aberranth!permeth!lation of the FMR1promoter. lmost alwa!s# extensi$e somatic$ariation of repeat number is obser$ed in a peripheral blood specimen of apatient with a full mutation. s a result# clinical laboratories ma! report thissomatic $ariation as a range of se$eral hundred repeats.

See Pu#lis*ed 'uidelines/&onsensus Statements0 see Amos @ilson et al >344?,Ba6ins et al

>34?on t*e a!aila#ility o" re"erence materials "or clinical la#oratories+

$linical testing

Targeted mutation anal"sis

o 'ol"merase c)ain reaction 'C*&speci%c for the @'' trinucleotiderepeatregion of FMR1has high sensiti$it!for FMR1repeats in thenormal and lower premutation range (t!picall! D5 to 5 repeats:$aries b! testing laborator!). 7owe$er# traditional FMR10speci%c -@R isless sensiti$e to larger premutations and fails to amplif! full mutations.9ewer methods promise to o$ercome these limitations (see Molecular'enetic -athogenesis).

o Sout)ern blotanal"sisdetects all FMR1alleles including normal#larger0sied premutations# and full mutations and in additiondetermines meth!lationstatus of the FMR1promoter region. bnormalh!permeth!lation of FMR1is the cause of transcriptional silencing andis critical to assess for premutation and full mutationalleles.

9oteA lthough Bouthern blot anal!sis pro$ides a low0resolutionestimation of repeat number# traditional -@Rplus Bouthern blotanal!sis has been the Egold standardF for FMR1molecular diagnosis.s newer and more sensiti$e -@R methods gain acceptance indiagnostic testing# the need for Bouthern blot anal!sis of e$er! patient

ma! decrease &@hen et al 5# ?ilipo$ic0Badic et al 5# 7antash etal 5# G!on et al 5# @hen et al 55# 9ahhas et al 55+.

o A++ trinucleotide repeatgenot"ping.'' genot!ping is o;eredas a separate test to determine the number and location of ''trinucleotide interruptions within the tract of @'' repeats of FMR1. 2henumber and position of '' trinucleotide repeats are "nown to beimportant in the o$erall stabilit! of the @'' repeat sequence &ichleret al 5331+. Recent results ha$e lin"ed the length of the uninterrupted
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Referenceshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.amoswilson.2008.2http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hawkins.2011.10http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hawkins.2011.10http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hawkins.2011.10http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/diagnostic-testing/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2010.589http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.lyon.2010.505http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nahhas.2011.187http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.eichler.1994.88http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.eichler.1994.88http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Referenceshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.amoswilson.2008.2http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hawkins.2011.10http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hawkins.2011.10http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/diagnostic-testing/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2010.589http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.lyon.2010.505http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nahhas.2011.187http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.eichler.1994.88http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.eichler.1994.88


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4H @'' repeat length with expansion and suggest a minimum thresholdfor expansion ris" &9olin et al 55+. 2he clinical usefulness of suchtesting awaits publication of the full stud!. 2his test is o;ered forfemale carriers of intermediate and small premutation alleles.

Met)"lation statuscan be assessed b! -@R0based methods independent of

measuring the number of @'' repeats

Se,uence anal"sis.er! few indi$iduals with fragile 6 s!ndrome ha$e beenidenti%ed with an intragenic FMR1mutation.

Deletion-duplicationanal"sis. ?ewer than 58 of indi$iduals with fragile 6s!ndrome ha$e a partial or full deletionof FMR1(re$iewed in 7ammond et al&533J+). Gac" of ampli%cation b! -@Rprior to sequence anal!siscan suggesta putati$e exonic or whole0genedeletion on the 6 chromosomein a;ectedmales: con%rmation ma! require additional testing b! deletion/duplicationanal!sis. 7owe$er# deletions not located in the repeat region of the gene ma!

be missed in males on routine clinical testing b! -@R for the trinucleotiderepeatexpansion. Keletions are t!picall! detected in FMR1as a secondar!%nding when the trinucleotide repeat region is being interrogated b!Bouthern blotanal!sis# ?IB7# or other method (see2able # footnote 1).

2herefore# it is li"el! that FMR1deletions downstream of the repeat region# aswell as other gene rearrangements# are under ascertained. 9e$ertheless#both small deletions near the repeat region in exon5 and large0scaledeletions that completel! remo$e FMR1continue to be reported in theliterature.

Test c%aracteristics.In"ormation on testsensiti!ity, s2eci"icity, and ot*er test c*aracteristics can

#e "ound at 666+eurogentest+org>ac5uemont et al 340 see "ull text?+

Ta#le 3+ Summary o" $olecular 'enetic Testing Csed inFMR1-Related %isorders

+ene

S"mb

ol

Test Met)od Mutations Detected

Mutation

Detection

Fre,uenc" b"

Test Met)od

Test

A/ailabili

t"

FMR1 2argeted mutationanal!sis

'C*.@'' expansion in FMR1(allelesies in the normal andlower premutation range) # 4

L338

@linical

Sout)ern blot.@''expansion in FMR1(all repeatranges): meth!lationstatus # 1

A++ trinucleotide repeat

genot"ping.9umber andposition of '' trinucleotiderepeats that ma! interrupt the

58 of allelesof thisstructure *
http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nolin.2011.925http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hammond.1997.430http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hammond.1997.430http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.summary_of_molecular_genetic_/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.eurogentest.org/web/info/public/unit3/geneCards.xhtmlhttp://www.eurogentest.org/web/info/public/unit3/geneCards.xhtmlhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2011.1http://www.nature.com/ejhg/journal/v19/n9/pdf/ejhg201155a.pdfhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nolin.2011.925http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hammond.1997.430http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hammond.1997.430http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.summary_of_molecular_genetic_/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.eurogentest.org/web/info/public/unit3/geneCards.xhtmlhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2011.1http://www.nature.com/ejhg/journal/v19/n9/pdf/ejhg201155a.pdfhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/targeted-mutation-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/


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@'' repeats of FMR1*

Meth!lationanal!sis

Meth!lation of FMR1promoterregion>

58 of alleleswith thismodi%cation

?IB7 Garge (partial0 or whole0gene)FMR1deletions

58

Keletion/duplicationanal!sis J

Garge (partial0 or whole0gene)FMR1deletions / duplications

58

Bequenceanal!sis

FMR1sequence $ariants # 4# N 58

+ T*e a#ility o" t*e test met*od used to detect a mutationt*at is 2resent in t*e indicated

gene

3+ Se5uence analysis, targeted mutationanalysis #y P&R, and in some instances Sout*ern#lotanalysis cannot detect an exonic or 6*ole-genedeletionon t*e X c*romosomein

carrier"emales+

D+ 1ac o" am2li"ication #y P&R2rior to se5uence analysiscan suggest a 2utati!e 2artial

or 6*ole-genedeletionon t*e X c*romosomein a""ectedmales0 con"irmation may

re5uire additional testing #y deletion/du2lication analysis+

%as et al ..,@ein*ausel

E Baas 344,7ygren et al 344, &o""ee 344., &*en et al 34?+

+ Testing t*at identi"ies deletions/du2lications not readily detecta#le #y se5uence

analysiso" t*e coding and "laning intronic regions o" genomic %7A0 included in t*e!ariety o" met*ods t*at may #e used are: 5uantitati!e P&R,long-range P&R, multi2lex

ligation-de2endent2ro#eam2li"ication ($1PA), and c*romosomal microarray(&$A)

t*at includes t*is gene/c*romosomesegment+
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/diagnostic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/diagnostic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2010.589http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.lyon.2010.505http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nahhas.2011.187http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.das.1997.151http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.weinhausel.2001.450http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.weinhausel.2001.450http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.weinhausel.2001.450http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nygren.2008.496http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nygren.2008.496http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.coffee.2009.1http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosomal-microarray/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/diagnostic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2010.589http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.filipovicsadic.2010.399http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hantash.2010.162http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.lyon.2010.505http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nahhas.2011.187http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Genetic_Pathogenesishttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.das.1997.151http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.weinhausel.2001.450http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.weinhausel.2001.450http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nygren.2008.496http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.coffee.2009.1http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chen.2011.528http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosomal-microarray/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/


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+ xam2les o" mutations detected #yse5uence analysismay include small intragenic

deletions/insertions and missense, nonsense, and s2lice site mutations0 ty2ically, exonic

or 6*ole-genedeletions/du2lications are not detected+

#nterpretation o test results

?or issues to consider in interpretation of sequence anal!sisresults# clic"here.

If the clinical phenot!peis consistent with fragile 6 s!ndrome and moleculargenetic testingof K9extracted from leu"oc!tes is normal# moleculargenetic testing of a second tissue t!pe (e.g.# s"in %broblasts) should beconsidered &Macenie et al >+.

Testing Strateg"

$onirming/estalis%ing t%e diagnosis

Molecular genetic testing is appropriate for the following (see ?igure 5.2esting algorithm)A

o Indi$iduals of either sex with intellectual disabilit!# de$elopmentaldela!# or autism# especiall! if the! ha$e an! of the followingA

n! ph!sical or beha$ioral characteristics of fragile 6 s!ndrome

famil! histor!of fragile 6 s!ndrome

Male or female relati$es with undiagnosed intellectual disabilit!

o Indi$iduals who ha$e a c!togenetic fragile 6 test result that isdiscordant with their phenot!pe# includingA

2hose who ha$e a strong clinical indication (including ris" ofbeing a carrier) and who ha$e had a normal or ambiguousc!togenetic fragile 6 test result: and

2hose with an at!pical phenot!pewho ha$e had a positi$ec!togenetic fragile 6 test result

9oteA @hromosome anal!sis using modi%ed culture techniques toinduce fragile sites (i.e.# c!togenetic fragile 6 test) is no longerused for diagnosis of fragile 6 s!ndrome because it is lesssensiti$e and more costl! than molecular genetic testing.

o Males and females older than age * !ears who ha$e progressi$ecerebellar ataxia and intention tremor with a positi$e famil! histor!ofFMR10related disorders in whom other common causes of ataxia ha$ebeen excluded (see taxia O$er$iew)
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/app2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mackenzie.2006.39http://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/ataxias/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/app2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mackenzie.2006.39http://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/ataxias/


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o Pomen with unexplained -OI &@orrigan et al *+

Molecular genetic laborator! testing

o Molecular genetic testing for fragile 6 s!ndrome must includemethod(s) to detect all t!pes of FMR1alleleexpansions: t!picall!#these are -@Rand Bouthern blotanal!sis. Phen -@R detects onenormal allele in a male or two in a female# Bouthern blot anal!sis ma!not alwa!s be indicated. Bouthern blot# or another method to detecth!permeth!lation# should be performed for premutations and fullmutations detected b! -@R.

?or intermediate and small premutation alleles in carrierfemales# '' trinucleotide genot!pingma! be useful to assessris" of alleleexpansion upon transmission.

Rarel!# in indi$iduals who ha$e cellular mosaicismfor the FMR1

repeat -@Rma! gi$e a false negati$e resultbecause it cannotdetect mosaicism for larger premutation and full mutationalleles&Orrico et al 533N# Bchmuc"er Q Beidel 5333+. Bouthern blotanal!sis detects these complex alterations in most cases.

o ?IB7or deletion/duplication anal!sisshould be used if -@Rfails todetect the @'' repeats in a male or in female relati$es of a proband"nown to ha$e an FMR1deletion.

o Bequence anal!sis is $er! rarel! needed. er! few a;ectedindi$idualsha$e been identi%ed with a mutationoutside of the @'' repeats.

Figure

Figure + Testing algorit*m "orFMR1-related disorders+ T*e #oxes mared 6it* asteriss (G)

identi"y indi!iduals to #e considered "orFMR1molecular testing+ See Testing Strategy,

&on"irming/esta#lis*ing t*e diagnosis in a 2ro#and "or "urt*er discussion (more+++)

$lariication o t%e genetic status o omenseeing re2roducti!e counseling 6*o *a!e a"amily *istoryo"FMR1-related disorders re5uires 2rior con"irmation o" t*e 2resence o" an

ex2anded (or altered)FMR1allelein t*e "amily or t*e 2resence o" undiagnosed intellectual

disa#ility+

7ote: () Female carriers are *eteroygotes "or t*is X-lined disorder and may de!elo2 clinical

"indings related to t*e disorder0 i+e+, intellectual disa#ility in "ull-mutationcarriers, "ragile X-

associated tremor ataxia syndrome and 2rimary o!arian insu""iciency (PI) in 2remutation
http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.corrigan.2005.1508http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/false-negative-result/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.orrico.1998.341http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.schmucker.1999.221http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.corrigan.2005.1508http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotyping/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/false-negative-result/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.orrico.1998.341http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.schmucker.1999.221http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/southern-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/figure/fragilex.F1/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/


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carriers+ (3) Identi"ication o" "emale carriers re5uires a22ro2riatemolecular genetic testingto

identi"y t*eir status+

!redictive testing"or at-ris asym2tomatic adult "amily mem#ers (male relati!es at ris "or

FXTAS and "emale relati!es at ris "or PI) re5uires 2rior identi"ication o" an ex2anded (or

altered)FMR1allelein t*e "amily+

!renatal diagnosis"or at-ris 2regnancies re5uires 2rior con"irmation o" t*e 2resence o" an

ex2anded (or altered)FMR1allelein t*e "amily+

7ote: Results "rom c*orionic !illus sam2ling (&HS) testing must #e inter2reted 6it* caution

#ecause o"ten t*e met*ylationstatus o"FMR1is not yet esta#lis*ed in c*orionic !illi at t*e time

o" sam2ling+ &HS, 6*ile a standard tec*ni5ue "or2renatal diagnosis, may lead to a situation in

6*ic* "ollo6-u2 amniocentesis is necessary to resol!e an am#iguous result+

!reimplantation genetic diagnosis (!&D)"or at-ris 2regnancies re5uires 2rior con"irmation o"t*e 2resence o" an ex2anded (or altered)FMR1allelein t*e "amily+

+eneticall" *elated Allelic& Disorders

7o 2*enoty2es ot*er t*an "ragile X syndrome, FXTAS, and PI are no6n to #e associated 6it*

mutations inFMR1+

Bo6e!er, 2reliminary studies o" t*e correlation o"FMR1allelesie !ariations in t*e normal and

2remutation range suggest a 2ossi#le relations*i2 to mild intellectual disa#ility in "emales >Allen

et al 344=? and males >1oat et al 344, Bagerman et al 344.?+ A study o" 4 daug*ters o" men

6it* FXTAS demonstrated an increased incidence o" neurologic and 2syc*iatric sym2toms

com2ared to controls, 2ro!iding more e!idence "or suc* an association >&*onc*aiya et al 344?+

A male 6it* com2lexFMR1mosaicism("ullmutation,2remutation, anddeletion) 6it* only

learning disa#ility >Ban et al 344? also raises issues concerning geneand2rotein ex2ressionin

FMR1-related 2*enoty2es+

'o toA

Clinical Description

Natural 0istor"

*ales it% ull-mutationalleles (ragile X syndrome).T*e 2*enoty2ic "eatures o" males 6it*a "ull mutation and, *ence, t*e "ragile X syndrome, !ary in relation to 2u#erty (see $linical

eatures in males it% ragile X syndrome)+

Pre2u#ertal males tend to *a!e normal gro6t* #ut large occi2ito"rontal *ead circum"erence

(=4t* 2ercentile)+ By2otonia, gastroeso2*ageal re"lux, and recurrent otitis media are 2ro#lems

in in"ancy t*at re5uire medical attention >Bagerman E Bagerman 3443?+ %elayed attainment o"
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/prenatal-diagnosis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/prenatal-diagnosis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.allen.2005.435http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.allen.2005.435http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loat.2006.555http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2009.378http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chonchaiya.2010.38http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.han.2006.1463http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/protein-expression/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/protein-expression/http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2002.278http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/prenatal-diagnosis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.allen.2005.435http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.allen.2005.435http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loat.2006.555http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2009.378http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chonchaiya.2010.38http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.han.2006.1463http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/protein-expression/http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2002.278


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motor milestones and s2eec* is a22arent in t*e "irst se!eral years o" li"e+ t*er 2*ysical "eatures

not readily recognia#le in t*e 2resc*ool-age c*ild #ecome more o#!ious 6it* age+ T*ese

in!ol!e t*e cranio"acies (long "ace, 2rominent "ore*ead, large ears, and 2rominent ;a6) and

genitalia (macro-orc*idism), and a#normal tem2erament (*y2eracti!ity, *and "la22ing, *and

#iting, tem2er tantrums, and occasionally autism)+

8e*a!iors in 2ost2u#ertal males 6it* "ragile X syndrome o"ten include tactile de"ensi!eness,

2oor eye contact, 2erse!erati!e s2eec*, 2ro#lems in im2ulse control, and distracti#ility+ T*e

#e*a!iors tend to #ecome more o#!ious o!er time+ T*e comor#id diagnosis o" autism occurs in

nearly 3=J o" a""ectedindi!iduals >Batton et al 344?+

7ote: Recent e!idence suggests an increased ris "or autism s2ectrum disorder and/or attention

de"icit disorder in 2remutation carriers as 6ell >Farin et al 344, Bagerman et al 344.?+

2*t*almologic (stra#ismus), ort*o2edic (;oint laxity), cardiac (mitral !al!e 2rola2se), and

cutaneous (excess so"tness and smoot*ness) a#normalities *a!e also #een noted+ xce2t "or t*estra#ismus, t*ese issues ty2ically do not re5uire signi"icant inter!ention+

Peri!entricular *eteroto2ia and ot*er neuroradiologic a#normalities >$oro et al 344? are

consistent 6it* a#normal neuronal migration and de!elo2ment suggested #y t*e meta#otro2ic

glutamate rece2tor (m'luR) t*eory o" "ragile X intellectual disa#ility (see $olecular 'enetics)+

$linical eatures in males it% ragile X syndrome(ada2ted "rom Tarleton E Saul >..D?)

Dela"ed de/elopmental milestones(usual age of attainment in bo!s)

o Bit alone (5 months)

o Pal" (.> months)

o ?irst clear words ( months)

'repubertal eatures

o Ke$elopmental dela!# especiall! speech

o bnormal temperamentA tantrums# h!peracti$it!# autism

o Intellectual disabilit!A I 40*

o bnormal craniofaciesA long face# prominent forehead# large ears#prominent jaw

'ostpubertal eatures
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hatton.2006.1804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.farzin.2006.S137http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2009.378http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moro.2006.713http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Geneticshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.tarleton.1993.169http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hatton.2006.1804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.farzin.2006.S137http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hagerman.2009.378http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moro.2006.713http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.Molecular_Geneticshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.tarleton.1993.169


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o Macro0orchidism

o bnormal beha$iorA sh!ness# gae a$ersion

o OphthalmologicA strabismus

o OrthopedicA joint h!perextensibilit!# pes planus

1t)er eatures

o @ardiacA mitral $al$e prolapse# aortic root dilatation

o KermatologicA usuall! soft and smooth s"in

Females %etero'ygous or ull-mutationalleles (ragile X syndrome).T*e 2*ysical and

#e*a!ioral "eatures seen in males 6it* "ragile X syndrome *a!e #een re2orted in "emales

*eteroygous "or t*e "ull mutation, #ut 6it* lo6er "re5uency and milder in!ol!ement+

Fragile X-associated tremor/ataxia syndrome (FXTAS)is c*aracteried #y late-onset

2rogressi!e cere#ellar ataxia and intention tremor in 2ersons 6*o *a!e anFMR12remutation

>ac5uemont et al 3441oesc* et al

344=, 8acalman et al 344,'rigs#y et al 344,1ouis et al 344, $c&onie-Rosell et al 344,

Kogan et al 344,Bunter et al 344.?+

8ot* males and "emales 6it* a 2remutation are at increased ris "or FXTAS+ T*e 2re!alence o"

FXTAS is estimated at a22roximately 0>3 4N8

J0J3 1J8

SN J*8

Ada2ted "rom 'rigs#y et al >344=?
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2004.460http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2006.804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loesch.2005.326http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loesch.2005.326http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bacalman.2006.87http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bacalman.2006.87http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2006.227http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2006.227http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.louis.2006.420http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.kogan.2008.859http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.kogan.2008.859http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2006.804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.risk_for_fxtas_by_age_in_male/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.risk_for_fxtas_by_age_in_male/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2004.460http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2006.804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loesch.2005.326http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.loesch.2005.326http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bacalman.2006.87http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2006.227http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.louis.2006.420http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.kogan.2008.859http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.jacquemont.2006.804http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.risk_for_fxtas_by_age_in_male/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.grigsby.2005.1


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@*ile FXTAS is more di""icult to ascertain in "emales #ecause o" milder clinical 2resentation,

2re!alence estimates range "rom a22roximately J to +=J o" "emale 2remutation carriers

>&o""ey et al 344,Rodrigue-Re!enga et al 344.?+

Increasing 2remutation re2eat lengt*s are correlated to increasing lieli*ood o" de!elo2ing

FXTAS >Tassone et al 344, 1ee*ey et al 344?+

A retros2ecti!e longitudinal re!ie6 o" == males 6it* 2remutations 2ro!ides early natural *istory

in"ormation o" FXTAS >1ee*ey et al 344?+ T*e "irst sign to a22ear is usually tremor at

a22roximately age 4 years+ Ataxia tends to de!elo2 t6o years later, leading to increased

tendency to "all and su#se5uent de2endence on 6aling aids+ 1i"e ex2ectancy a"ter onset o"

sym2toms ranged "rom "i!e to 3= years+

7euroradiologic signs (decreased cere#ellar !olume, increased !entricular !olume, and increased

6*ite matter *y2erdensity) a22ear to correlate 6it* 2remutation &'' re2eat lengt* >&o*en et al

344?+

FMR1-related primary ovarian insuiciency (!"#)+de"ined as cessation o" menses #e"ore age

&orrigan et al 344=,7elson et al

344=?+ It is estimated t*at =J-4J o" 6omen may concei!e a"ter t*e diagnosis o" PI is

esta#lis*ed >7elson et al 344=?+ See Sulli!an et al >34?"or a re!ie6+

T*e earlier "indings t*at alleles in t*e *ig* normal and intermediate range con"erred an increased

ris "orFMR1-related PI >8ret*eric et al 344=,8odega et al 344? 6ere not su22orted #y a

recent more ro#ust study >8ennett et al 344?+ &urrently, no consensus exists "or estimating an

a#solute ris "or PI 6*en a 6oman *as *ig* normal or intermediate re2eat alleles+ S*erman

>344=?concluded t*at t*e ris "or PI 6as 3J (estimates ranged "rom =J to 3J in !arious

studies) in 2remutation carriers, com2ared to a J#acground ris+In t*is re!ie6 an odds ratio

o" 3+= 6as estimated "or intermediate re2eat sies o" @itten#erger et al 344?+ (See

'enoty2e-P*enoty2e &orrelations, !remutation"or additional ris estimates+)

Sulli!an et al >344=?suggest t*at !ariation in t*e age at meno2ause in t*e general 2o2ulation

may #e related toFMR1&'' re2eat sie #elo6 4, a "inding "urt*er su22orted #y data "romnnis et al >344?+ A signi"icant increase o" alleles in t*e D= to =< range 6as "ound in 6omen

6it* PI >8ret*eric et al 344=?+ In all t*ree studies, larger 2remutations (4 &'' re2eats)

carried lo6er ris "or PI+ Bunter et al >344?suggested t*at ot*er "actors in addition to &''

re2eat sie a""ect t*e age at meno2ause0 an additional study 6it* o!er D4 6omen "ailed to

demonstrate an increased ris "or PI "or 6omen 6it* alleles in t*e *ig* normal and

intermediate range (D=-= re2eats) >8ennett et al 344?+
http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.coffey.2008.1009http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.tassone.2007.566http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.leehey.2008.1397http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.leehey.2007.203http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cohen.2006.1426http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cohen.2006.1426http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.murray.1999.1217http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.uzielli.1999.300http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.uzielli.1999.300http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.uzielli.1999.300http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hundscheid.2000.413http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bussani.2004.189http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.machadoferreiramdo.2004.237http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.corrigan.2005.1508http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2011.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bretherick.2005.376http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bennett.2010.1335http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/background-risk/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/background-risk/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/background-risk/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.wittenberger.2007.456http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.GenotypePhenotype_Correlationshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2005.402http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2005.402http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.ennis.2006.253http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bretherick.2005.376http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2008.553http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bennett.2010.1335http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.coffey.2008.1009http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rodriguezrevenga.2009.1359http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.tassone.2007.566http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.leehey.2008.1397http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.leehey.2007.203http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cohen.2006.1426http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cohen.2006.1426http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.murray.1999.1217http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.uzielli.1999.300http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.uzielli.1999.300http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hundscheid.2000.413http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bussani.2004.189http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.machadoferreiramdo.2004.237http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.mcconkierosell.2007.593http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.corrigan.2005.1508http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.nelson.2005.1327http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2011.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bretherick.2005.376http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bennett.2010.1335http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/background-risk/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.wittenberger.2007.456http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.GenotypePhenotype_Correlationshttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2005.402http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.ennis.2006.253http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bretherick.2005.376http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2008.553http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bennett.2010.1335


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@omen 6it* "ull mutationalleles are not at increased ris "or PI+

+enot"pe(')enot"pe Correlations

T*e2*enoty2eo" males 6it* anFMR1mutationde2ends almost entirely on t*e nature o" t*e

mutation0 t*e 2*enoty2e o" "emales 6it* anFMR1mutation de2ends on #ot* t*e nature o" t*e

FMR1mutation and random X-c*romosome inacti!ation(see Ta#le Riddle et al .., 8ourgeois et al 344.,Bunter

et al 344.,&*onc*aiya et al 344?+

3+FMR1mutations are com2lex alterations in!ol!ing non-classic geneinacti!ating

mutations (trinucleotide re2eatex2ansion) and a#normal gene met*ylation+ T*is
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/x-chromosome-inactivation/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.types_of_fmr1_repeat_expansio/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.riddle.1998.590http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bourgeois.2009.852http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chonchaiya.2010.38http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/x-chromosome-inactivation/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.types_of_fmr1_repeat_expansio/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.riddle.1998.590http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bourgeois.2009.852http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hunter.2009.79http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.chonchaiya.2010.38http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/


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com2lexity at t*e gene le!el a""ects 2roduction o" t*eFMR12rotein and may result in an

aty2ical 2resentation in 6*ic* a""ectedindi!iduals occasionally *a!e an I9 a#o!e 4, t*e

traditional demarcation denoting intellectual disa#ility (2re!iously re"erred to as mental

retardation)+

!remutation.$ales and "emales 6*o *a!e a "ragile X 2remutation *a!e normal intellect anda22earance+ As noted inTa#le 8odega et al 344,nnis et al 344?+

Ta#le =+ dds Ratios "or PI #y Premutation Sie

'remutation Si#e in C++ *epeats 1dds *atio or '1I

*30J3 >.3

N033 *.5

L5 5>.1

S*erman >344=?

Full mutation.$ales 6*o *a!e a "ullFMR1mutation generally *a!e moderate to se!ere

intellectual disa#ility and may or may not *a!e a distincti!e a22earance+

A22roximately =4J o" "emales 6*o *a!e a "ullFMR1mutationare intellectually disa#led0

*o6e!er, t*ey are usually less se!erely a""ectedt*an males 6it* a "ull mutation+ &on!ersely,

a22roximately =4J o" "emales 6*o are *eteroygous "or t*e "ull mutation are intellectually

normal+ T*e !aria#ility among "emales is #elie!ed to result "rom t*e ratio in t*e #rain o" acti!e X

c*romosomes 6it* t*eFMR1"ull mutation to inacti!e X c*romosomes 6it* t*e normalFMR1

allele+

*osaicism.$osaicism is 2resent in a22roximately =J-34J o" indi!iduals 6it*FMR1mutations+ Suc* mosaicismmay #e () Mre2eat sie mosaicism,M in 6*ic* #ot* "ull mutations and

2remutations are 2resent (also termed M"ull-mutation/ 2remutation mosaicismM), or (3)

met*ylationmosaicism, in 6*ic* "ull mutations *a!e !arying degrees o" met*ylation+

Alt*oug* some data suggest t*at indi!iduals 6it* re2eat sie mosaicismormet*ylation

mosaicism 2er"orm at a *ig*er intellectual le!el t*an t*ose 6it* com2letely met*ylated "ull

mutations, suc* indi!iduals are usually intellectually disa#led+
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.types_of_fmr1_repeat_expansio/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.types_of_fmr1_repeat_expansio/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.odds_ratios_for_poi_by_premut/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.ennis.2006.253http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.types_of_fmr1_repeat_expansio/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/NBK1384/table/fragilex.T.odds_ratios_for_poi_by_premut/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.bodega.2006.952http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.ennis.2006.253http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sherman.2005.584http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mosaicism/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/


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Rarely, indi!iduals 6it* met*ylationmosaicismor com2letely unmet*ylated "ull mutations and

normal intellect *a!e #een re2orted+ T*e milder2*enoty2ea22ears to #e related to F$RP

2roduction arising "rom transcri2tiono" unmet*ylated alleles >Tassone et al ...?+ Presuma#ly,

t*ese indi!iduals 2roduce at least some F$RP #ecauseFMR1is unmet*ylated+ T*e existence o"

t*ese exce2tional indi!iduals suggests t*at re2eat ex2ansion and met*ylation o" t*e geneare not

a#solutely cou2led+

Anticipation

Fragile X syndrome is a trinucleotide re2eatdisorder t*at may demonstrate antici2ationin some

"amilies+ Ty2ically, antici2ation occurs 6*en less se!erely a""ected2remutation or mosaic

mutationcarriers transmit unsta#leFMR1alleles to t*eir o""s2ring (e+g+, transmission "rom a

grand"at*er 6*o carries a 2remutation to *is daug*ter, 6*ose 2remutation ex2ands into a "ull

mutation 6*en s*e transmits it to *er son, 6*o *as intellectual disa#ility as a result)+ Bo6e!er,

t*e antici2ation "ound in "amilies 6it* mem#ers a""ected 6it* "ragile X syndrome is not classic,

as is t*at "ound in, "or exam2le, myotonic dystro2*y ty2e + $any "amilies transmit 2remutation

FMR1alleles "or generations 6it* little or no 2resentation o" clinical sym2toms until a "ullmutation is 2roduced, resulting in an a""ected indi!idual+

're/alence

Fragile X syndrome.Pre!alence estimates o" males 6it* "ragile X syndrome *a!e #een re!ised

do6n6ard since t*e isolation o"FMR1in ..+ riginal estimates o" 4:44,444 males a""ected

6it* t*e syndrome (o"ten still 5uoted in t*e "ragile X literature) 6ere #ased on t*e cytogenetic

detection o" t*e "ragile site FRAXA "or con"irmation o" t*e diagnosis o" "ragile X syndrome in

males 6it* intellectual disa#ility+ Indi!iduals 6it* intellectual disa#ility coincidentally *a!ing

ot*er c*romosomal "ragile sites near FRAXA (e+g+, FRAX%, FRAX, and FRAXF) 6ere liely

included in t*e initial estimates+ (&ytogenetic di""erentiation o" t*ese "ragile sites is di""icult

#ecause t*ey are located in close 2roximity in t*e X53-53 region+) $ore recent studies using

molecular genetic testingo"FMR1*a!e estimated a 2re!alence o" to 3=:44,444 males

a""ected 6it* t*e "ragile X syndrome (using intellectual disa#ility as t*e *allmar clinical

"inding) >de Hries et al ..?+

A #linded study o" 4,4


16/38

In 5#>1 ?rench0@anadian women# 15 were found to ha$e an FMR1premutation# representing a pre$alence of 5A*3 &4N>A5#: 3*8 @I#5A4J405A53N (>N0**A5#)+ &Rousseau et al 533*+.

In 51#441 Israeli women of child0bearing age# 5J were found to ha$e @''repeats greater than *1# including three as!mptomatic women with fullmutations# representing a pre$alence of 5A554 (NN*A5#) &2oledano0lhadef et al 5+.

In nearl! #4 women from the United Btates# the pre$alence ofpremutations was 5A4N (>A5#) and of intermediate alleles# 5A514(>33A5#) &@ronister et al *+.

In the largest stud! to date from a laborator! database of more than *3#tests# the o$erall female carrierfrequenc! was 5.48 (.>58 for full mutation#5.J8 for a premutation) &Btrom et al J+.

Females it% FMR1-related !"#.T*eFMR12remutation accounts "or 8russino et al 344=, &ellini et al 344?+

'o toA

Di5erential DiagnosisDevelopmental delay/ intellectual disaility.T*e signs o" "ragile X syndrome in early

c*ild*ood are nons2eci"ic, 6it* de!elo2mental delay #eing an almost uni!ersal mani"estationamong a""ectedindi!iduals+ Any c*ild (male or "emale) 6it* delay o" s2eec*, language, or motor

de!elo2ment o" unno6n etiology s*ould #e considered "or "ragile X testing, es2ecially in t*e

2resence o" a "amily *istoryo" intellectual disa#ility and a consistent 2*ysical and #e*a!ioral

2*enoty2e, and t*e a#sence o" structural a#normalities o" t*e #rain or ot*er #irt* de"ects >&urry

et al ..,$oesc*ler E S*e!ell 344?+ @*en "ragile X molecular genetic testingis used

regularly in t*is large and loosely de"ined grou2 o" unselected males 6it* intellectual disa#ility,

t*e yield o" 2ositi!e test results is relati!ely lo6 (NDJ-J) >&urry et al .., S*e!ell et al 344D?+

In a more recent study,Rauc* et al >344?"ound t*e yield to #e +3J+

8ecause cytogenetic a#normalities *a!e #een identi"ied as "re5uently or more "re5uently t*anFMR1mutations in de!elo2mentally disa#led or intellectually im2aired indi!iduals re"erred "or

"ragile X testing, c*romosomeanalysis s*ould #e 2er"ormed as a 2art o" t*eir la#oratory

e!aluation >$oesc*ler E S*e!ell 344?+

&onditions to #e considered in t*e di""erential diagnosis include t*e "ollo6ing:
http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rousseau.1995.1006http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.toledanoalhadef.2001.351http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.toledanoalhadef.2001.351http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cronister.2005.246http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.strom.2007.46http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2011.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.brussino.2005.145http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cellini.2006.1135http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moeschler.2006.2304http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.shevell.2003.367http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rauch.2006.2063http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rauch.2006.2063http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moeschler.2006.2304http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rousseau.1995.1006http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.toledanoalhadef.2001.351http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.toledanoalhadef.2001.351http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cronister.2005.246http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.strom.2007.46http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.sullivan.2011.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.brussino.2005.145http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cellini.2006.1135http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moeschler.2006.2304http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.curry.1997.468http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.shevell.2003.367http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.rauch.2006.2063http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.moeschler.2006.2304


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Sotos s"ndrome. Botos s!ndrome is characteried b! t!pical facialappearance# o$ergrowth# and learning disabilit! ranging from mild to se$ere.It is associated with beha$ioral problems# congenitalcardiac anomalies#neonatal jaundice# renal anomalies# scoliosis# seiures# and a slightl!increased ris" for sacrococc!geal teratoma and neuroblastoma.pproximatel! N8038 of indi$iduals with Botos s!ndrome ha$e a

demonstrable mutationor deletionof NSD1.

'rader(6illi s"ndrome'6S&. small subset of people with fragile 6s!ndrome ha$e the h!perphagia and obesit! characteristic of -PB. -PB ischaracteried b! se$ere infantile h!potonia and feeding diVculties# followedb! earl! childhood onset of excessi$e eating and de$elopment of morbidobesit! unless controlled. ll indi$iduals ha$e de$elopmental dela! andcogniti$e impairment. 2emper tantrums# stubbornness# manipulati$ebeha$ior# and obsessi$e0compulsi$e characteristics are common.7!pogonadism (genital h!poplasia# incomplete pubert!# and# in most#infertilit!)# short stature# and characteristic facial appearance are common.Kiagnosis is b! K90based meth!lationtesting to detect abnormal parent0speci%c imprintingwithin the -rader0Pilli critical regionon chromosome5*.

Autism. utistic0li"e beha$ior is frequentl! found in indi$iduals with fragile 6s!ndrome.

Attention defcit()"peracti/it" disorder AD0D&.7!peracti$it! isfrequentl! seen in indi$iduals with fragile 6 s!ndrome.

Fragile X7 s"ndrome F*AX7&.Mild intellectual disabilit! (not as se$ere asthat t!picall! seen in fragile 6 s!ndrome) without consistent ph!sical featureshas been described in males with expanded @@' repeats in FMR2at the

?R6 fragile site. ?R6 and ?R6 are distinct fragile sites# albeit in closeproximit! on the 6 chromosome. 2he genes spanning the two fragile sites aredesignated FMR1(?R6) and FMR2(?R6). 7owe$er# the genes do notha$e an! detectable similarit! at the K9le$el and the associated clinicalentities are discrete.

Adult(onset neurologic disorders.2he di;erential diagnosis for ?62B isbroad. One group of *> indi$iduals had 3N di;erent diagnoses prior to thediagnosis of ?62B. Most of these were in the following categoriesApar"insonism# tremor# ataxia# dementia# autonomic d!sfunction# and stro"e&Ciancalana et al *# 7all et al *+.

It is estimated that 8018 of men with adult0onset cerebellar ataxia whorepresent as simplex cases (i.e.# a single occurrence in a famil!) ha$e apremutation in FMR1&Crussino et al *# @ellini et al >+.

'o toA
http://www.ncbi.nlm.nih.gov/books/n/gene/sotos/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/congenital/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/pws/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/critical-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/autism-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.biancalana.2005.962http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hall.2005.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.brussino.2005.145http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cellini.2006.1135http://www.ncbi.nlm.nih.gov/books/NBK1384/http://www.ncbi.nlm.nih.gov/books/n/gene/sotos/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/congenital/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/pws/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/critical-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/autism-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.biancalana.2005.962http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.hall.2005.299http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.brussino.2005.145http://www.ncbi.nlm.nih.gov/books/NBK1384/#fragilex.REF.cellini.2006.1135http://www.ncbi.nlm.nih.gov/books/NBK1384/


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Management

7/aluations Follo8ing Initial Diagnosis

Fragile X syndrome.To esta#lis* t*e extent o" disease in an indi!idual diagnosed 6it* "ragile X

syndrome, t*e "ollo6ing e!aluations are recommended:

@omplete de$elopmental and educational assessments (including speech andlanguage e$aluation and occupational/ph!sical therap! e$aluation) foreducational planning

Ceha$ioral and ps!chological assessment to determine the presence ofconcentration/attention problems# anxiet!# obsessi$e0compulsi$e disorder#aggression# and depression

In infants# feeding assessment (including attention to possiblegastroesophageal re


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>&orrigan et al 344=,7elson et al 344=?+ It is estimated t*at =J-4J o" 6omen 6it* PI may

concei!e a"ter t*e diagnosis >7elson et al 344=?+

Treatment o Maniestations

Fragile X syndrome.7o s2eci"ic treatment is a!aila#le+ Su22orti!e t*era2y "or c*ildren and

adults 6it* "ragile X syndrome currently consists o" t*e "ollo6ing >Bagerman et al 344.,Ctari etal 344?:

Recognition of the need for special education and anticipator! managementsuch as the a$oidance of excessi$e stimulation whene$er possible ma!ameliorate some of the beha$ioral diVculties.

arl! educational inter$ention# special education# and $ocational trainingshould be aimed speci%call! at the "nown impediments to learning. -arentsand teachers of children with fragile 6 s!ndrome ha$e recognied the needfor indi$idual attention# small class sie# and the a$oidance of suddenchange. More speci%c guidelines are a$ailable through education resources(see Resources).

-harmacologic management of beha$ioral issues that signi%cantl! a;ectsocial interaction is appropriate. 9o particular pharmacologic treatment hasbeen shown to be uniquel! bene%cial: therap! must be indi$idualied andclosel! monitored. closel! monitored and integrated program of beha$ioralmanagement and pharmacologic treatment with an experiencedde$elopmental team ma! pro$e to be bene%cial.

Routine medical management of strabismus# otitis media# gastroesophagealre


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'o toA

+enetic CounselingGenetic counseling is the process of providing individuals and families with information on the

nature, inheritance, and implications of genetic disorders to help them make informed medical

and personal decisions. The following section deals with genetic risk assessment and the use offamily history and genetic testing to clarify genetic status for family members. This section is not

meant to address all pers

síndrome de x frágil -javier aram arciniega_grupo e

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