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SCREENIG FOR GENETIC DISEASE

Genetic disease affects individuals and theirs families

dramatically. Every persn! and every cuple havin" children isat sme ris# f seein" a disrder $ith a "enetic cmpnentssuddenly appearin".

Firstly ! there is a screenin" f individuals and cuples #n$n t%e at si"nificant r hi"h ris# %ecause f a psitive family histry.

Secondly, there is the screenin" ffered t the "eneralppulatin! $h are at l$ ris#&this is smetimes referred t ascommunity genetics.

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SCREENING T'OSE AT 'IG' RIS(

CARRIER TESTING FOR AR AND X-LINKED DISORDERS

  In num%er f AR disrders e.". Tay&Sachs disease! sic#le&celldisease! carriers can %e rec"ni)ed $ith a hi"h de"ree fcertainty usin" %ichemical r hematl"ical techni*ues such

that DNA analysis is nt necessary. In ther sin"le&"enedisrders! it is pssi%le t detect r cnfirm carrier status %y%ichemical means in nly prprtin f carriers.

There are several pssi%le $ays in $hich carriers f "eneticdiseases can %e rec"ni)ed.

+. Clinical manifestatins in carriers

,. -ichemical a%nrmalities in carriers

. /in#a"e %et$een a disease lcus and a plymrphic mar#er

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C/INICA/ 0ANIFESTATIONS IN CARRIERS

Occasinally! carriers fr certain disrders can have mildclinical manifestatins f the disease& particularly $ith sme fthe 1&lin#ed disrders. Such manifestatins! even thu"hminimal! are unmista#a%ly pathl"ical. 2nfrtunately! in mstautsmal and 1&lin#ed recessive disrders there are either nmanifestatins at all in carriers! r they verlap $ith variatinseen in the "eneral ppulatin. An e3ample $uld %e femalecarriers f hemphilia! $h have a tendency t %ruise easily.This $uld nt! h$ever! %e a relia%le si"n f carrier status! asthis is seen in a si"nificant prprtin f the "eneral

ppulatin. Thus clinical manifestatins are nly f imprtance in detectin"

carriers $hen they are unmista#a%ly pathl"ical! and this isthe e3ceptin rather than rule $ith mst sin"le&"ene disrders.

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-IOC'E0ICA/ A-NOR0A/ITIES IN CARRIERS

The demnstratin f detecta%le %ichemical a%nrmalities incarriers fr AR and 1&lin#ed disrders has %een the mstimprtant apprach t determine the carrier status f certaindiseases. In sme disrders the %ichemical a%nrmality seenis a direct prduct f the "ene and carrier status can %e tested

fr $ith cnfidence. In many in%rn errrs f meta%lism! theen)yme activity levels in carriers verlap $ith the nrmalran"e.

  In many sin"le "ene disrders! h$ever! the %ichemicala%nrmality used in the dia"nsis f the disrder in theaffected individual is nt a direct result f actin f the "ene

prduct %ut the cnse*uence f a secndary r d$nstreamprcess.

Randm inactivatin f the 1 chrmsme in females meansthat many! ften the ma4rity! f female carriers f 1&lin#eddisrders cannt %e relia%ly detected %y %ichemical methds.

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/IN(AGE -ET5EEN A DISEASE /OC2SAND A 6O/70OR6'IC 0AR(ER

DNA polymorphic markers

The lar"e num%er f different types f DNA se*uence variantsin the human "enme means that if sufficient num%ers ffamilies are availa%le! lin#a"e f any disease $ith aplymrphic DNA mar#er is pssi%le. 2se f the mar#ers at theDNA level vercmes the need t identify a %ichemical defectas $ell as the difficulties that ccur in carrier detectin due t1&inactivatin fr $men at ris# fr 1&lin#ed disrders.

  lin#ed plymrphic DNA mar#ers are fre*uently used indeterminin" the carrier status f females in families $hereD0D has ccurred.

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DNA 0AR(ERS 8ptential pitfalls

Recombination

  The chance f recm%inatin ccurrin" %et$een theplymrphic DNA mar#er and the disease lcus t $hichlin#a"e has %een sh$n & is the first ptential pitfall. The ris#

f a recm%inatin can %e minimi)ed %y the identificatin feither intra"enic r clsely lin#ed mar#ers n either side f thedisease lcus! r $hat are termed flanking markers. In smeinstances! such as $ith the dystrphin lcus 8 there is a 9htspt: fr recm%inatin. Even $ith clsely flan#in" rintra"enic mar#ers there appears t %e a minimal chance fappr3imately +,; that recm%inatin $ill ccur in anymeisis in a female.

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DNA 0AR(ERS & ptential pitfalls

Sample availability

  The use f lin#ed plymrphic DNA mar#ers means thatsamples frm the apprpriate family mem%ers are re*uired.This can prve difficult! dependin" n relatinships $ithin thefamily.

Polymorphic variation

  Anther pr%lem is 8 $hether the family pssesses thenecessary variatin in a lin#ed mar#er t %e $hat is #n$n asinformative.

Locus heteroeneity

  6lymrphic DNA mar#ers can %e e3tremely relia%le if thedisease in *uestin is caused %y mutatins in nly ne "ene inthe entire "enme. In many cnditins mutatins in mre thanne "ene can "ive rise t the same %asic phentype anddemnstrate locus heterogeneity.

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6RES706TO0ATIC DIAGNOIS OF ADDISORDERS

0any AD sin"le&"ene disrders either have a delayed a"e fnset! r e3hi%it reduced penetrance.

T predict $hether a persn has inherited the "ene %efre thenset f symptms r si"ns can %e all$ed %y

+. Clinical e3aminatin

,. Specialist investi"atin

. -ichemical tests

<. /in#ed DNA mar#ers

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6RES706TO0ATIC DIAGNOSIS

!linical e"amination

  In a num%er f dminantly inherited disrders simple clinical means can%e used fr presymptmatic dia"nsis ta#in" int accunt pssi%lepleitrpic effects f a "ene.

Specialist investiation

  In cnditins $here clinical assessment leaves dia"nstic du%t ram%i"uity! special investi"atins r relevant %dy systems can serve tclarify status r presymptmatic dia"nsis.

#iochemical tests

  -ichemical tests can determine in a num%er f AD disrders $hetherr nt a persn at ris# has inherited a "ene.

Linke$ DNA markers

  The availa%ility f lin#ed DNA mar#ers has fund $idespread use inpresymptmatic r predictive testin" fr a num%er f sin"le&"enedisrders inherited in a AD manner.

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ET'ICA/ CONSIDERATIONS IN CARRIERDETECTION AND 6REDICTI=E TESTING

Fr sme individuals and cuples the #n$led"e that there is asi"nificant ris# f havin" an affected child may present ptinsand chices that they $uld rather nt have. The attendantris#! and the a$areness that the prenatal dia"nsis isavaila%le! may create a sense f "uilt a%ut $hichever decisin

is ta#en. It is pssi%le that emplyers! life insurance cmpanies and

sciety in "eneral $ill put interdict and! n ccasin! directpressure n persns at ris# fr inherited disrders t have suchtestin".

Anther pr%lem raised %y the develpment f predictive r

presymptmatic testin" is that it can! in thery! %e used frchildren and minr 8 $ith parents smetimes ar"uin" that istheir ri"ht t #n$ the status f their children. This cnflicts$ith the hi"h ideal f uphldin" the principle f individualautnmy $herever pssi%le.

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6O62/ATION SCREENING

!RI%ERIA &'R A S!REENIN( PR'(RA)

  %*E DISEASE + shuld %e sufficiently cmmn and haveptentially serius effects that are amena%le t preventin rameliratin.

  %*E %ES% + shuld %e accurate and relia%le $ith hi"hsensitivity and specificity.

  %*E PR'(RA) + shuld %e ffered in a fair and e*uita%lemanner and shuld %e $idely availa%le. It als must %e mrallyaccepta%le t a su%stantial prprtin f the ppulatin t$hich is ffered. 6articipatin must %e entirely vluntary in thecase f prenatal pr"rams! %ut the ethical principles are mre

cmple3 in nenatal screenin" fr a cnditins $here earlytreatment is essential and effective in preventin" mr%idity.

  It is ften stated that the cst f a screenin" pr"ram shuld%e reasna%le and affrda%le.

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NEONATA/ SCREENING

Ne$%rn screenin" pr"rams have %een intrduced n a $idespread%asis fr phenyl#etnuria! "alactsemia and cn"enital hypthyridism.

  PK,- rutine %ichemical screenin" f ne$%rn infants and a l$&phenylalanine diet culd prevent the severe learnin" disa%ilities. Any$men $ith 6(2 $h is cntemplatin" pre"nancy shuld adhere t a

strict l$&phenylalanine diet %th %efre and durin" pre"nancy.  (ALA!%'SE)IA- the early intrductin f apprpriate dietary

restrictin can prevent the develpment f serius cmplicatins suchas cataracts! liver failure! and learnin" disa%ilities.

  !IS%I! &I#R'SIS + it is hped! that early treatment $ithphysitherapy and anti%itics $ill imprve the ln"&term pr"nsis.

  SI!KLE-!ELL DISEASE AND %*ALASSE)IA + it is hped that earlyprphyla3is $ill reduce mr%idity and mrtality.