Practce Tes Tes 1 (1-50 (1-5 0 questons) Queston 1 James, a 3-week-old infan wi ecrodac!l! (a rare malformaton of e ands and fee) is "rou# o !ou "! is $arens, %e&e and %on!a' James as one older si"lin# wo as normal ands and fee' lou# neier $aren as and or foo a"normalites, mem"ers of %e&es famil! are a*eced wi ecrodac!l!' famil! isor! re&eals e follo followin# win# $edi#ree, $edi#ree, were s!m"ols s!m"ols re$resen re$resentn# tn# indi&iduals indi&iduals a*eced wi ecrodac ecrodac!l! !l! are saded and s!m"ols re$resentn# re$resentn# indi&iduals wi no clinical s!m$oms are no saded' +a mode of ineriance is mos su##esed su# #esed "! is $edi#ree '
uoso uosomal mal rece recessi& ssi&e e wi wi &aria &aria"le "le e$r e$ress essi&i i&i!!
.'
/-lin /-linke ked d domin dominan an wi wi redu reduced ced $ener $eneranc ance e
'
-linke -linked d wi wi e&ide e&idence nce of allel allelic ic ee eero ro#en #enei ei!!
2'
uoso uosomal mal dominan dominan wi wi redu reduced ced $ener $eneranc ance e
'
/-lin /-linke ked d reces recessi& si&e e wi wi a i# i# de#re de#ree e of $lei $leior oro$! o$!
Queston 4 Te #ure sown ere dis$la!s e resuls of a 26 fra#men anal!sis e$erimen in&ol&in# marker 241%378' 9eno!$es were o"ained for four indi&iduals' Te si:e (in "ase $airs) of eac idented fra#men is found in e "o under eac allele $eak' +ic saemen "es descri"es e 26 sequence of 241%378 '
241% 241%37 378 8 iiss a min minis isa ael elli lie e
.'
241% 241%378 378 is a mon monoal oalle lelic lic mark marker er
'
241%378 241%378 is a sin#le sin#le nucleo nucleotde tde $ol $ol!mo !mor$ r$ism ism (%6P) (%6P)
2'
241%378 241%378 is a dinu dinucle cleotd otde e micros microsa aell ellie ie re$ea re$ea
Tis is an eam$le of a dinucleotde re$ea, wi mult$le alleles, eac di*eren from e oer "! a facor of wo nucleotdes' ; is am$lied usin# e $ol!merase cain reacton (P<) wi 26 $rimers a =ank e re$ea uni and e alleles are se$araed from one anoer "! se$araton "! ca$illar! or #el elecro$oresis (see a$er >)' Queston 3 +ic kar!o!$e re$resens re$resens an indi&idual wi a "alanced cromosome com$lemen '
78, /
.'
>5, >5, //, //, der( der(1> 1>?4 ?41) 1)(q (q10 10?q ?q10 10))
'
>7, // //, del(>$)
2'
>7, >7, /, /, @der( @der(1) 1)( (1?3 1?3)($ )($31? 31?$4 $41) 1) A3
'
>7, >7, /, /, du$( du$(14) 14)(q (q11 11'4? '4?q4 q41' 1'4) 4)
Tis is e kar!o!$e of an indi&idual wi a "alanced
and 41' Tis indi&idual lacks one normal 1> and one normal 41 and as insead a lon# cromo cromosom some e com$o com$osed sed of e q arms arms of "o "o cromo cromosom somes es (noe (noe a a ere ere are onl! >5 cenro cenromer meres es A ranslocaton of wo acrocenric cromosomes resuls in e loss of one cenromere)' s e sor arms of acrocenric cromosomes are &er! small and conain no essental #enetc maerial, eir loss does no resul in a clinical $eno!$e' Bowe&er, e o*s$rin# of ese "alanced indi&iduals are a risk of ineritn# missin# or era $ars of e in&ol&ed cromosomes (see a$er 1C)' Queston >
eir ne cild will $resen wi e clinical si#ns of e disease '
3D>
.'
1D4
'
1D>
2'
1DC
'
Eiruall! 0
+e can assume a ' Queston 5 n ado$ton sud! was initaed in an aFem$ o deermine weer de$ression as a #enetc "asis or is due sricl! o en&ironmenal facors' duls wi de$ression wo were ado$ed as infans were recruied ino e sud! as cases' Te frequenc! of de$ression was com$ared "eween e "iolo#ical and non-"iolo#ical ado$t&e relat&es of e cases' ;f de$ression as a sron# #enetc com$onen, wa is e mos likel! ndin# of is sud! '
2e$ression 2e$ression raes raes are similar similar "eween "eween e e "iolo#ica "iolo#icall and non-"iol non-"iolo#ical o#ical relat& relat&es' es'
.'
2e$re 2e$ressio ssion n rae raess are i#e i#err for e e "iolo# "iolo#ica icall relat& relat&es' es'
'
2e$re 2e$ressio ssion n raes raes are i#e i#err for e e non-"io non-"iolo#i lo#ical cal rela relat&e t&es' s'
Tis addresses e queston of weer a disease Gruns in families "ecause of sared #enetc or en&ironmenal facors' do$ed indi&iduals sare e #enetc facors of eir "iolo#ical famil!, "u e en&ironmenal facors of eir eir non-"iolo#ic non-"iolo#ical al famil! famil!' ;f de$ression de$ression is sron#l! sron#l! in=uenced in=uenced "! #enetc facor facors, s, ere ere sould "e a i#er incidence of de$ression amon# e "iolo#ical famil! (see a$er 15)' Queston 7 +a is e ineriance $aFern a "es s e disease sown in e $edi#ree sown ere '
u uoso osomal mal rece recess ssi& i&e e
.'
u uoso osomal mal dom dominan inan
'
%e %e-lin -linkked rece recess ssi& i&e e
2'
%e %e-lin -linkked domi domina nan n
6otce indi&iduals are a*eced in eac #eneraton A a allmark of dominan disorders' ;n additon, ere is no male-o-male ransmission, ere are a$$roimael! wice as man! a*eced females as males, and a*eced faers ransmi e disease o all of eir dau#ers A all of wic su##es a se-linked dominan disorder (see a$er H)' Queston H T!$e 1 al"inism is an auosomal recessi&e disorder a resuls from a muaton in !rosinase, resultn# in e lack of $i#menaton' Jon and %usan, wo are married, are "o eal! and no a*eced wi !$e 1 al"inism, alou# alou# Jons Jons faer faer was a*eced a*eced as was %usan %usans maernal maernal #randmoer #randmoer'' %usan is $re#nan' $re#nan' +a is e $ro"a"ili! a is feus will "e a*eced wi !$e 1 al"inism '
1D>
.'
1DC
'
1D17
2'
1D4>
'
1D7>
;ndi&iduals wi auosomal recessi&e disorders a&e muatons in eac co$! of e causat&e #ene' Ior a cild of Jon and %usan o a&e !$e 1 al"inism, eac $aren mus ineri one co$! of e muaton and en $ass i o e cild' Jons faer ad !$e 1 al"inism so Jon ineried one co$! of e !rosinase muaton from im' Tere is a 1D4 cance e will $ass is alon# o a cild' +e know %usans %usans moer is an o"li#ae carrier for !$e 1 al"inism (se
eir ne cild will $resen wi e clinical si#ns of e disease '
3D>
.'
1D4
'
1D>
2'
1DC
'
Eiruall! 0
+e can assume a ' Queston 5 n ado$ton sud! was initaed in an aFem$ o deermine weer de$ression as a #enetc "asis or is due sricl! o en&ironmenal facors' duls wi de$ression wo were ado$ed as infans were recruied ino e sud! as cases' Te frequenc! of de$ression was com$ared "eween e "iolo#ical and non-"iolo#ical ado$t&e relat&es of e cases' ;f de$ression as a sron# #enetc com$onen, wa is e mos likel! ndin# of is sud! '
2e$ression 2e$ression raes raes are similar similar "eween "eween e e "iolo#ica "iolo#icall and non-"iol non-"iolo#ical o#ical relat& relat&es' es'
.'
2e$re 2e$ressio ssion n rae raess are i#e i#err for e e "iolo# "iolo#ica icall relat& relat&es' es'
'
2e$re 2e$ressio ssion n raes raes are i#e i#err for e e non-"io non-"iolo#i lo#ical cal rela relat&e t&es' s'
Tis addresses e queston of weer a disease Gruns in families "ecause of sared #enetc or en&ironmenal facors' do$ed indi&iduals sare e #enetc facors of eir "iolo#ical famil!, "u e en&ironmenal facors of eir eir non-"iolo#ic non-"iolo#ical al famil! famil!' ;f de$ression de$ression is sron#l! sron#l! in=uenced in=uenced "! #enetc facor facors, s, ere ere sould "e a i#er incidence of de$ression amon# e "iolo#ical famil! (see a$er 15)' Queston 7 +a is e ineriance $aFern a "es s e disease sown in e $edi#ree sown ere '
u uoso osomal mal rece recess ssi& i&e e
.'
u uoso osomal mal dom dominan inan
'
%e %e-lin -linkked rece recess ssi& i&e e
2'
%e %e-lin -linkked domi domina nan n
6otce indi&iduals are a*eced in eac #eneraton A a allmark of dominan disorders' ;n additon, ere is no male-o-male ransmission, ere are a$$roimael! wice as man! a*eced females as males, and a*eced faers ransmi e disease o all of eir dau#ers A all of wic su##es a se-linked dominan disorder (see a$er H)' Queston H T!$e 1 al"inism is an auosomal recessi&e disorder a resuls from a muaton in !rosinase, resultn# in e lack of $i#menaton' Jon and %usan, wo are married, are "o eal! and no a*eced wi !$e 1 al"inism, alou# alou# Jons Jons faer faer was a*eced a*eced as was %usan %usans maernal maernal #randmoer #randmoer'' %usan is $re#nan' $re#nan' +a is e $ro"a"ili! a is feus will "e a*eced wi !$e 1 al"inism '
1D>
.'
1DC
'
1D17
2'
1D4>
'
1D7>
;ndi&iduals wi auosomal recessi&e disorders a&e muatons in eac co$! of e causat&e #ene' Ior a cild of Jon and %usan o a&e !$e 1 al"inism, eac $aren mus ineri one co$! of e muaton and en $ass i o e cild' Jons faer ad !$e 1 al"inism so Jon ineried one co$! of e !rosinase muaton from im' Tere is a 1D4 cance e will $ass is alon# o a cild' +e know %usans %usans moer is an o"li#ae carrier for !$e 1 al"inism (se
ad o ineri one of e wo muan co$ies from f rom %usans #randmoer, #randmoer, wo was a*eced') %u"sequenl!, %u"sequenl!, ere is a 1D> cance %usan will $ass alon# a !rosinase muaton o a cild A a 1D4 cance se recei&ed e muaton er moer ineried from %usans #randmoer mult$lied "! a 1D4 cance a se would $ass alon# a muaton o a cild' %o ere is a 1DC oal cance e feus will ineri wo co$ies of e r!rosinase muaton (see a$er H)' Queston C %u$$ose a researc sud! sows a $eo$le wo su*er from es anie! are omo:!#ous for a muaton in e / #ene' ;ndi&iduals wiou es anie! a&e e followin# sequence a e &er! "e#innin# of e ranslaed re#ion of eir / #enesK 5L-T9 5L-T9 9 TTT 9 TT 9 TT 9-3L e Tr Pe 9lu ;le 9ln %er r# *eced indi&iduals a&e e followin# sequenceK 5L-T9 9 TTT 9 TT T9 TT 9-3L e Tr Pe 9lu ;le %TMP Te muaton idented amon# a*eced indi&iduals is mos likel! an eam$le of wic of e followin# !$es '
issense
.'
9ain of fu functon
'
6onsense
2'
IramesiN
'
2ominan ne#at&e t&e
nonsense muaton is a su"stuton a leads o e #eneraton of one of e so$ codons, resultn# in $remaure $remaure erminaton of e ranslaton maciner! (see a$er 4)' Queston 8 6ed and %ace! are e $arens of ark, a cild a*eced wi a full! $eneran, auosomal recessi&e disorder a is easil! dia#nosed a "ir, and occurs in e $o$ulaton wi an incidence of 1D3700' 6eier 6ed nor %ace! as is disorder emsel&es' Teir ne cild, Ton!, is "orn wiou an! a$$aren si#ns of e disease' Ton! #rows u$ and marries aria, a woman wi no known famil! isor! of e disorder' Te cance a Ton! and arias rs cild will "e a*eced wi e same s ame disorder a a*ecs ark is closes o wic of e followin# num"ers '
1D>5
.'
1D140
'
1D1C0
2'
1D4>0
'
1D370
Tree in#s mus occur for Ton! and aria o a&e an a*eced cild' 1' Ton! mus "e a carrier for e disorder' s Ton! doesn sow an! s!m$oms of e disorder (wic is full! $eneran), e does no carr! "o co$ies of e muaton' %u"sequenl!, ere are ree equall! likel! remainin# #eno!$e o$tons for Ton! A omo:!#ous normal, eero:!#ous wi e muaton recei&ed from is moer, or eero:!#ous eero:!#ous wi e muaton recei&ed from is faer' faer' Te o&erall $ro"a"ili! a Ton! is a carrier is erefore erefore 4D3 (see a$er H)' 4' aria mus also "e a carrier' .ecause aria as no famil! isor! of disorder, we assume er risk of "ein# a carrier is equi&alen o e carrier frequenc! in e $o$ulaton' Tis can "e deduced usin# Bard!-+ein"er# equili"rium (see a$er C)' Te incidence of is disorder in e $o$ulaton is 1D3700' s mentoned in e e ($' 147), a rou# estmae of e carrier frequenc! can "e o"ained "! dou"lin# e square roo of e $o$ulaton frequenc! A O 4 1D70 1D30' Tis i s e cance a aria is a carrier' carrier'
3' .o Ton! and aria mus $ass eir muaton on o a cild' ;f "o Ton! and aria are carriers, e cance e! would a&e an a*eced cild is 1D> (see a$er H)' To o"ain e nal $ro"a"ili! for is $ro"lem, mult$l! e $ro"a"ilites from all ree e&ens A 4D3 1D30 1D> 4D370 1D1C0' Queston 10 nne is 17 weeks $re#nan and under#oes maernal serum screenin# o es er maernal serum al$a feo$roein feo$roein le&els (%IP)' Ber %IP le&el is >'5 mult$les of e median (o)' ssumin# nne is carr!in# a sin#le feus and er $re#nanc! is correcl! daed for #esatonal a#e, for wic of e followin# disorders sould nne "e o*ered additonal estn# '
Trisom! 13 13
.'
Pulm Pulmon onar ar!! ! !$o $o$ $lasi lasia a
'
M$en s$ina ina "ida
2'
!stc " "rosis
'
Trisom! 41
;ncreased le&els of %IP are associaed wi e $resence of o$en neural u"e defecs, suc as anence$al!' anence$al!' Te #enerall! acce$ed cu-o* le&el a"o&e wic furer in&est#aton is o*ered is 4'5 o' Tis &alue deecs a$$roimael! a$$roimael! H5R of screened o$en neural u"e defecs' Queston 11 Saren is a 38-!ear-old woman wo #i&es "ir o an infan #irl wi =eed and o&erla$$in# n#ers, rocker-"oFom fee, low-se ears and a recessed aw' Prenaal Prenaal ulrasound ad re&ealed e $resence of lar#e coroid $leus c!ss in e cere"ral &enricles of e feus, wic did no s$onaneousl! disa$$ear' Te infan dies aNer 3 weeks' romosome anal!sis of e infan is mos likel! o re&eal wic of e followin# kar!o!$es '
>5, >5, //, //, der( der(13 13?4 ?41) 1)(q (q10 10Kq Kq10 10))
.'
>H, //, @1C
'
>5, /M
2'
>H, //, @13
'
>7, //, A>$
Te a"o&e $!sical descri$ton is consisen wi a dia#nosis of risom! 1C' ;n additon, e $resence of coroid $leus c!ss on ulrasound is a so-called so- called GsoN marker sometmes o"ser&ed amon# risom! 1C feuses (see a$er 1C)' Queston 14 Ior wa $ur$ose are $renaal screenin# ess "es used '
To dia#n dia#nose ose a sus$e sus$ece ced d di disea sease se in a feus feus
.'
To dia#n dia#nose ose a sus$e sus$ece ced d di disea sease se in a $aren $aren
'
To o"ain o"ain fe feal al cells cells for for crom cromoso osome me kar! kar!o! o!$in $in# #
2'
To identf! identf! indi&i indi&idua duals ls wo soul sould d under#o under#o dia#n dia#nost ostcc estn# estn#
'
To eamine eamine e 26 26 of a feus feus for for sus$ec sus$eced ed muat muatons ons in a s$ecic s$ecic #ene #ene
%creenin# ess are no, in and of emsel&es, dia#nostc' Te! are desi#ned o se$arae mos of e indi&iduals wo are a an increased risk of "ein# a*eced wi a disease from ose wo are less likel! o a&e e disease' onrmaton of disease saus requires a follow-u$ dia#nostc es' Queston 13 +ic of e followin# $renaal dia#nostc ecniques routnel! allows feal cromosomes o "e anal!:ed durin# e rs rimeser of $re#nanc! '
ordoc docenesis
.'
mniocenesis
'
orionic &illus sam$lin#
2'
'
aernal ri$le estn#
orionic &illus sam$lin# is a rs rimeser dia#nostc meod for o"ainin# 26 for direc estn# or cromosome anal!sis' ; is routnel! $erformed a 11A14 weeks #esaton' Queston 1> ark is a*eced wi 2ucenne muscular d!sro$!, an /-linked disorder' uaton anal!sis in is famil! identes a sin#le "ase $air su"stuton in eon 1 of e 22 #ene, inroducin# a $remaure so$ codon' Te mos likel! consequence of is muaton is a reducton in wic of e followin# '
moun of 22 26
.'
Uen# of 22 26
'
Uen# of 22 m<6
2'
Uen# of 22-encoded $roein
$remaure so$ codon will oNen lead o e e$ression of a runcaed $roein' 9enerall!, e sorened amino acid cain is una"le o reain normal functon, $artcularl! if e muaton occurs near e 5L end of e #ene' 6oe a in some cases, m<6 ranscri$s conainin# $remaure so$ codons are acuall! de#raded "! a $rocess known as nonsense-mediaed deca!, $re&entn# e formaton of $roein alo#eer (see a$er 4)' Queston 15 6earl! e&er! indi&idual a*eced wi neuro"romaosis !$e 1 (6I1) ei"is clinical s!m$oms' %ome, owe&er, ma! $resen wi cafV au lai s$os and Uisc nodules, wile oers a&e life-reaenin# umors surroundin# e s$inal cord' Tese re$resen an eam$le of wic of e followin# '
.'
Earia"le e$ressi&i!
'
2i#enic ineriance
2'
Uocus eero#enei!
'
%e-in=uenced e$ression
Earia"le e$ressi&i! refers o e &ariaton o"ser&ed in clinical s!m$oms amon# indi&iduals wi an identcal #enetc disorder (see a$er H)' Queston 17 +ic of e followin# $rocesses occurs durin# meiosis ;; '
Bomolo#ous cromosomes se#re#ae o o$$osie $oles
.'
%u"meacenric and acrocenric cromosomes under#o recom"inaton
'
%iser cromatds of e omolo#ous cromosomes se$arae
2'
26 $airin# is initaed, leadin# o e formaton of e s!na$onemal com$le
'
iasmaa are resol&ed, allowin# inde$enden mo&emen of omolo#ous cromosomes
2urin# e second meiotc sa#e, siser cromatds, oined "! coesion $roeins a eir cenromere, ali#n on e mea$ase s$indle and are se$araed (see a$er 3)' Queston 1H li:a"e is a 45-!ear-old woman wi color "lindness, an /-linked recessi&e disorder' side from "ein# color "lind, er medical isor! is unremarka"le' Ber faer is also color "lind' Tere is no isor! of color "lindness on er moers side of e famil!' +a is e likel! cause of li :a"es color "lindness '
/ se re&ersal
.'
%kewed / inact&aton
'
Turner s!ndrome
li:a"e is likel! a manifestn# eero:!#oe wi skewed / inact&aton' / inact&aton occurs wen e female em"r!o consiss of around 5000 cells' is $oin, eier of e wo / cromosomes can "e inact&aed in an! $artcular cell and e coice is #enerall! random' tmes owe&er, e inact&aton $aFern is i#l! un"alanced in fa&or of one cromosome' ;n li:a"es case, i is likel! a e / cromosome carr!in# e normal #ene for color &ision is inact&aed a a i#er frequenc!, lea&in# e muaed co$! act&e in mos of er cells and resultn# in e clinical $eno!$e (see a$er 7)' Queston 1C %e&e is a 17-!ear-old male wi cleN $alae, microce$al!, conoruncal defecs, midface !$o$lasia and moderae de&elo$menal dela!' %e&es moer sows a similar consellaton of feaures' I;%B anal!sis of %e&es cromosomes would likel! identf! an a"normali! in wic of e followin# cromosomal re#ions '
Hq11
.'
>$
'
15q11-14
2'
44q11'4
'
1H$11'4
Te s!m$oms descri"ed are consisen wi &elocardiofacial s!ndrome, $ar of e 44q11 s!ndrome (2i9eor#eD%edlacko&aD&elocardiofacial s!ndrome) caused "! a ree me#a"ase microdeleton a cromosome 44q11 (see a$er 1C)' Queston 18 ;f an auosomal recessi&e disorder occurs in e W% skenasic Jewis $o$ulaton wi an incidence of a$$roimael! 1D7>00, e cance a wo $eo$le, randoml! drawn from is $o$ulaton will "o "e carriers for e muaton is closes o wic of e followin# '
1DC0
.'
1D>00
'
1D1700
2'
1D3400
'
1D7>00
Tis answer can, in $ar "e deermined "! e use of e Bard!-+ein"er# equili"rium equaton' Te incidence in e skenasic Jewis $o$ulaton is 1D7>00' s mentoned in e e ($' 147), a rou# estmae of e carrier frequenc! can "e o"ained "! dou"lin# e square roo of e $o$ulaton frequenc! A O 4 1DC0 1D>0' Te likeliood a wo indi&iduals drawn from e $o$ulaton will "o "e carriers is en 1D>0 1D>0 1D1700 (see a$er C)' Queston 40 Jon is a 34-!ear-old man, wo $resens wi $rimar! infertli!' 7L>X, e is a all and lank! indi&idual wi s$arse "od! air, small #onads and sli# #!necomasta' ellular anal!sis re&eals e $resence of a .arr "od!' estcular "io$s! re&eals an a"sence of #erm cells in e seminiferous u"ules' .ased u$on is descri$ton, wic is e mos likel! dia#nosis for Jon '
arfan s!ndrome
.'
Slinefeler s!ndrome
'
ndro#en insensit&i!
2'
on#enial adrenal !$er$lasia
'
Turner s!ndrome
Slinefeler s!ndrome is due o e $resence of an additonal / cromosome in males' duls wi Slinefeler
s!ndrome are sli#l! aller an a&era#e and all are infertle wi small eses' .arr "od! anal!sis sows e $resence of one .arr "od!, re=ectn# e $resence of e additonal / cromosome (see a$er 1C)' Queston 41 Sar!o!$e anal!sis of an a$$aren female infan re&eals a e "a"! is cromosomall! male (>7, /)' a#netc resonance ima#in# re&eals a eses are $resen, "u a male and female #enial ducs (&as deferens, e$idid!mis, fallo$ian u"es, uerus ec') are a"sen' .lood anal!sis re&eals normal circulatn# le&els of esoserone and di!droesoserone' +ic of e followin# conditons "es e$lains is consellaton of caraceristcs '
aernal andro#en in#eston durin# $re#nanc!
.'
uatons in 5-al$a reducase
'
2isa"led andro#en rece$ors
2'
Uack of esro#en rece$ors
'
uaton of e %<#ene
Tis is a case of andro#en insensit&i!, caused "! e a"sence of functonin# andro#en rece$ors, "lockin# e &irili:in# e*ecs of esoserone' Teses are $resen, "u wiou e acton of esoserone, male inernal srucures do no form' ullerian ini"itn# su"sance is $roduced, owe&er, leadin# o e a"sence of all female inernal srucures as well' ernal #enialia a$$ear as female, "u e &a#ina ends in a "lind $ouc (see a$er 1C)' Queston 44 s a #eneral rule, wen do $atens wi mea"olic disorders rs $resen wi clinical a"normalites '
2urin# uerine de&elo$men
.'
Irom "ir o earl! cildood
'
2urin# $u"er!
2'
;n earl! adulood
'
Ner e a#e of >0
os mea"olic disorders are idented durin# infanc! or earl! cildood wen e cilds "od! is rs res$onsi"le for mea"oli:in# e $roeins o"ained from formula or food (see a$er 11)' Queston 43 54-!ear-old woman comes ino e clinic wi er second "roken "one in 15 mons' 2urin# cildood, se ad ree fracures, all in di*eren "ones' Mn eaminaton, e woman is noed o a&e "lue-#ra! sclerae' +ic of e followin# #enes is likel! o "e muaed in is woman '
olla#en ; $ro-al$a1 ($roY1(;))
.'
!saione "ea s!nase (.%)
'
9alacose-1-$os$ae urid!l ransferase (9UT)
2'
Ii"rillin 1 (I.61)
'
%onic ed#eo# (%BB)
Tis $aten likel! as a mild form of oseo#enesis im$erfeca, an auosomal dominan colla#en ; disorder' Tere are se&eral su"!$es of is disorder, ran#in# in se&eri!' ild forms are usuall! due o nonsense muatons in e $ro-al$a1 #ene, leadin# o a runcaed or a"sen $rocolla#en $roein' ;ndi&iduals wi ese muatons oNen e$erience a small num"er of fracures in cildood and in laer life (due o $osmeno$ausal "one loss)' .lue sclerae are oNen a allmark of is s!ndrome (see a$er 18)' Queston 4> 8-mon-old infan $resens wi $oor feedin# and lear#!' 2e&elo$men was normal untl 7 mons of a#e, a wic tme e infan "e#an o miss milesones' .iocemical anal!sis of serum from e infan sows reduced le&els of eosaminidase ' +ic of e followin# is e mos likel! dia#nosis
'
+ilsons disease
.'
%ando* disease
'
Burler s!ndrome
2'
Uesc-6!an s!ndrome
'
Ta!-%acs disease
41-!dro!lase
.'
9lucos!lceramide "ea #lucosidase
'
olla#en ;;; $ro-al$a4
2'
Ii"ro"las #row facor rece$or 3 (I9I<3)
'
Paired "o #ene 3 (P/3)
uatons in e I9I<3 #ene is res$onsi"le for acondro$lasia, caraceri:ed "! ri:omelia, me#alence$al! and s$inal cord com$ression (see a$er 7)' Queston 47 $aten under#oes #ene era$! as $ar of a clinical rial for l:eimers disease' small (>'8 k") neuroro$ic #ene is $acka#ed ino a &eicle and insered direcl! ino e nondi&idin# cells of e i$$ocam$us' Bi# #ene ransfer raes, lon#-erm ine#raton and lastn# sa"le #ene e$ression are e #oals of e $roocol and e in&est#aors wis o a&oid elicitn# an! immune res$onse' +ic of e followin# deli&er! &eicles would "e e mos likel! candidae '
modied adeno-associaed &irus
.'
modied er$es &irus
'
modied adeno&irus
2'
26 $acka#ed in a li$osome
'
modied rero&irus
modied adeno-associaed &irus can accommodae insers of u$ o 5 k" in si:e, ine#raes sa"l! a a s$ecic sie on cromosome 18, and is a"le o infec nondi&idin# cells wiou stmulatn# os immune res$onses' Queston 4H Jon is a >4-!ear-old man wi emo$ilia ' Jons dau#er, %usan, is married o Ired, wo also as emo$ilia ' %usan and Ired are e$ectn# eir rs cild, and ulrasound demonsraes e feus is a "o!' Te $ro"a"ili! a Ired and %usans new son will a&e emo$ilia is closes o wic of e followin# '
1
.'
3D>
'
4D3
2'
1D4
'
1D>
Bemo$ilia is an /-linked recessi&e disorder, caused "! muatons in e #ene for cloZn# facor E;;;' Jon carries is muaton on is / cromosome and $asses i o %usan, wo is a carrier for emo$ilia' Ired $asses is cromosome o e feus, so is emo$ilia saus is acuall! irrele&an' Tere is a 50R cance %usan will $ass e normal / cromosome o er son and a 50R cance se will $ass e / cromosome a carries e muaton in
e facor E;;; #ene, leadin# o emo$ilia (see a$er 18)' Queston 4C 13-!ear-old "o! is "rou# for eaminaton' %li# muscle weakness, rs noed a a#e > !ears in e lower lim"s as $ro#ressed wi increasin# a#e, lea&in# im weelcair "ound' aminaton re&eals calf $seudo!$erro$!' +ic of e followin# o$tons re$resens e mos likel! #enetc cause of ese $!sical feaures '
du$licaton of e $eri$eral m!elin $roein-44 #ene (PP44)
.'
T9 e$ansion in e 3L unranslaed re#ion of e d!sro$ia m!oonica $roein kinase (2PS) #ene
'
n ou-of-frame deleton in e d!sro$in #ene
2'
missense muaton in e neuro"romin #ene
'
n in-frame deleton in e neuronal a$o$osis ini"ior! $roein (6;P) #ene
Tis "o! likel! as 2ucenne muscular d!sro$! (22), an /-linked recessi&e disorder' Two-irds of indi&iduals a*eced wi 22 a&e a deleton in e d!sro$in #ene, wic alers e ranslatonal readin# frame (see a$er 18)' Queston 48 #irl is idented wi sor saure, small ands and fee, o"esi!, and a learnin# disa"ili!' "ir, se ei"ied !$oonia, $oor suck re=e and a failure o ri&e' e a#e of 3, se de&elo$ed ereme !$er$a#ia and food seekin# "ea&ior, leadin# o e marked o"esi!' +ic of e followin# "es descri"es e mos likel! etolo#! of is case '
2isom! of cromosome 15 in e s$erm, followed "! loss of e maernal co$! of cromosome 15 in e earl! em"r!o
.'
deleton of e maernal co$! of 15q11-q13
'
Paernal uni$arenal disom! for cromosome 15
2'
deleton of e 15q11-q13 re#ion on e $aernall!-ineried cromosome
'
muaton in e im$rintn# cener of 15q11-q13, leadin# o a ed maernal im$rin $aFern
Tis #irl as Prader-+illi s!ndrome, a de&elo$menal disorder caused "! loss of #ene e$ression from e $aernall!-deri&ed co$! of cromosome 15q11-q13' an! #enes in is re#ion are im$rined, meanin# ere is di*erental e$ression de$endin# on weer e re#ion is ineried from e faer or e moer' "sence of e $aernal co$! of ese #enes leads o Prader-+illi s!ndrome, wile a"sence of a #ene in is re#ion from e maernal co$! leads o n#elman s!ndrome' Te mos common cause of Prader-+illi s!ndrome is a deleton of 15q11-q13 on e cromosome ineried from e faer (see a$er H)' Queston 30 +a can#e(s) in e retno"lasoma (<") #ene are required for e formaton of "ilaeral retno"lasomas in a !oun# cild '
%omatc occurrence of a sin#le muaton in one <" allele in an oerwise #enetcall! normal cell
.'
%omatc occurrence of muatons in "o <" alleles in an oerwise #enetcall! normal cell
'
m$licaton of "o co$ies of <" in an oerwise #enetcall! normal cell
2'
Uoss of functon of one co$! of e <" #ene due o an ineried muaton
'
Uoss of functon of "o co$ies of e <" #ene due o ineried and somatc muatons
disorder seems o se#re#ae in an auosomal dominan manner, alou# a e cellular le&el, wo muatons are required for umor formaton (see a$er 1>)' Queston 31 leander as con#enial m!oonic d!sro$!, wic is an auosomal dominan m!o$a!' les moer is mildl! a*eced wi moderae facial weakness and m!oonia' +a is e mos likel! molecular mecanism for con#enial m!oonic d!sro$! '
s$lice-sie muaton near e 5L end of e 2PS #ene
.'
$oin muaton in e $romoer re#ion of e 2PS #ene
'
Te inserton of additonal $ol!#luamine residues in e 2PS codin# re#ion
2'
n e$ansion of a T9 ri$le re$ea in e 3L re#ion of e 2PS #ene
'
deleton a encom$asses e entre 2PS codin# re#ion
!oonic d!sro$! is caused "! e e$ansion of a T9 sequence found in e 3LWT< of e corres$ondin# 2PS #ene' ;n e con#enial form of m!oonic d!sro$!, e$ansion of is re$ea re#ion can eceed 4000 re$eas' Tese cases are almos wiou ece$ton ineried maernall! (see a$er 18)' Queston 34 >>-!ear-old woman is found o a&e a small num"er of cancerous $ol!$s alon# e $roimal (ri# side) of e colon' Ber moer and one of er &e si"lin#s a&e also "een dia#nosed wi ese !$es of umors and anoer si"lin# as de&elo$ed #asric cancer' ll a*eced indi&iduals were idented wi cancer in eir middle fortes' nal!sis of se&eral $ol!mor$ic markers from e 26 of e umors re&ealed microsaellie insa"ili!, e $resence of numerous additonal alleles no $resen in noncancerous cells' +ic of e followin# s!ndromes "es descri"es is famil! '
B $ol!$osis
.'
Iamilial adenomaous $ol!$osis (IP)
'
owden disease
2'
Ui-Iraumeni s!ndrome
'
Berediar! non-$ol!$osis colorecal cancer (B6P)
B6P is an auosomal dominan form of colorecal cancer' Wnlike IP, onl! a small num"er of $ol!$s are $resen in e colon' B6P is associaed wi muatons in a se of mismac re$air #enes' +en indi&iduals ineri a muaed co$! of one of ese mismac re$air #enes, a loss of functon of e second co$! leads o e ina"ili! o re$air 26 mismaces, leadin# o an increased risk of mali#nanc! due o unre$aired errors in onco#enes or umor su$$ressors' allmark of B6P muatons is e $resence of microsaellie insa"ili! in umor 26 (see a$er 1>)' Queston 33 ssume a multfacorial disorder (disease /) is found around e world a a i#er frequenc! amon# males an females' +ic of e followin# is rue '
Te recurrence risk for disease / is i#es for a cou$le wi an a*eced son
.'
Te recurrence risk for disease / is i#es for a cou$le wi an a*eced dau#er
'
Te recurrence risk for disease / is inde$enden of #ender
ccordin# o e resold lia"ili! model of disease, if e conditon is more common amon# indi&iduals of one s$ecic #ender, en e risk will "e i#er for relat&es of an indi&idual of e less frequenl! a*eced se' .ecause e disorder descri"ed a"o&e is more common in males, e recurrence risk will "e i#er for e cou$le wi an a*eced dau#er (see a$er 8)' Queston 3> n allele of e a4c-adrener#ic rece$or (del344-345) as "een found o decrease rece$or functon' 170
unrelaed frican-merican $atens wi ear failure and 400 unrelaed frican-mericans wiou ear failure were #eno!$ed a is locus' Te adused odds rato for ear failure amon# $ersons wo were omo:!#ous for e del344-345 allele was 0'3C com$ared wi ose wo ad oer alleles' ssume ese resuls can "e re$licaed and &alidaed' om$ared o e risk for ear failure amon# an frican-merican wi oer alleles, e risk for an frican-merican wo is omo:!#ous for e del344-345 allele will "e wic of e followin# '
;ncreased
.'
2ecreased
'
;dentcal
2'
6o risk assessmen can "e made
Te ndin# of an odds rato si#nicanl! less an 1 su##ess a indi&iduals omo:!#ous for e s$ecic &arian (e del344-345 allele) a&e a lower risk of ear failure' Queston 35 Janice was dia#nosed wi "reas cancer a e a#e of >4' Premeno$ausal "reas cancer was a common occurrence in er faers famil! and #enetc estn# sowed a Janice $ossesses a muaed &ersion of .<1' +ic saemen "es descri"es e risk of de&elo$in# cancer for Janices famil! mem"ers '
;ndi&iduals in is famil! wo ineri e .<1 muaton a&e an increased risk of colorecal cancer'
.'
Te males in is famil! wo ineri e .<1 muaton a&e an increased risk of "reas cancer'
'
Janices dau#ers a&e a 1 in > risk of de&elo$in# "reas cancer'
2'
Janices faer likel! as an increased risk of $rosae cancer'
ales wi a .<1 muaton a&e an increased risk of de&elo$in# $rosae cancer' s e muaton likel! $assed o Janice from er faer, e $ro"a"l! carries e .<1 muaton imself (see a$er 1>)' Queston 37 7-!ear-old Sen!an cild de&elo$s .urkiF l!m$oma, a .-cell umor of e aw' Tis cancer is usuall! caused "! wic mecanism lised "elow '
;m$ro$er #ene con&ersion, leadin# o a deleton e&en in e .U #ene re#ion
.'
m$licaton of e .< locus on omo#eneousl! sainin# re#ions
'
Translocaton of e $roo-onco#ene o a $ositon downsream of e ;#B locus
2'
;neriance of a muaton in e S;T locus, followed "! e acquisiton of a second, somatc muaton a is locus
'
Promoer !$ome!laton of "o co$ies of e TP53 #ene
.urkiF l!m$oma is #enerall! e resul of a ranslocaton of e onco#ene from cromosome C o e ea&! cain immuno#lo"ulin locus on cromosome 1>, leadin# o an o&ere$ression of e #ene (see a$er 1>)' Queston 3H +ic of e followin# saemens is rue concernin# e functon of $roo-onco#enesK '
Proo-onco#enes ser&e as a si#nal for cellular a$o$osis
.'
Proo-onco#enes are com$onens of cell #row $awa!s
'
Proo-onco#enes are cell ceck$oin re#ulaors
2'
Proo-onco#enes scan e #enome for 26 dama#e
'
Proo-onco#enes re$air 26 dama#e across e #enome
Proo-onco#enes are com$onens of cell #row $awa!s, #enerall! in&ol&ed in rela!in# a G$ro-#row messa#e o e cell and res$ondin# "! stmulatn# e ranscri$ton of #row facors (see a$er 1>)' Queston 3C amine e followin# $edi#ree' +ic of e followin# disorders mos likel! a*ecs is famil! '
U% (miocondrial ence$alom!o$a! wi lactc acidosis and sroke-like e$isodes)
.'
Ira#ile / s!ndrome
'
Parkinsons disease
2'
Ui-Iraumeni s!ndrome
'
Uei#s s!ndrome
Tis is e $edi#ree of a !$ical famil! a*eced wi fra#ile / s!ndrome, a 99 rinucleotde re$ea disorder' Ior a small fracton of e $o$ulaton, e num"er of re$eas is unsa"le from #eneraton o #eneraton and as e num"er of re$eas e$ands, a ran#e of s!m$oms "ecomes a$$aren' Iull-muaton indi&iduals are menall! im$aired and a&e a caraceristc facial a$$earance'
%in#le "ase muatons in miocondrial <6 #enes
.'
Uar#e nons$ecic deletons in e miocondrial #enome
'
uatons in nuclear-encodin# #enes required for functon of e M/PBM% $awa!
2'
uatons in e #enes res$onsi"le for mainainin# miocondrial re$licaton
uatons in U% and <0 *eced si" $air sudies are $rimaril! used for wa $ur$ose '
To deermine e mos a$$ro$riae mendelian ineriance $aFerns for a disease of ineres
.'
To calculae e amoun of recom"inaton a occurs "eween a s$ecic candidae #ene and e disease of ineres
'
To identf! alleles or cromosomal re#ions sared "eween a*eced relat&es more oNen an e$eced "! cance
2'
To com$are e frequenc! of s$ecic alleles amon# $o$ulatons wi and wiou e disease of ineres
*eced si" $air anal!sis is a model-free meod a aFem$s o identf! alleles or cromosomal re#ions sared "! a*eced relat&es more oNen an e$eced "! cance (see a$er 8)' Queston >1 $osit&e associaton as "een idented "eween e do$amine rans$orer and indi&iduals wi aFenton deci !$eract&i! disorder (2B2)' Te &arian idented in is rece$or is an D nucleotde can#e in e 3LWT< of e #ene' Tis &arian as "een idented in mult$le sudies from around e world, eac com$osed of closel! maced #rou$s of cases and conrols' 6eier e normal nor e &arian allele sows an a$$recia"le di*erence in srucure or functon of e rans$orer, nor is a di*erence o"ser&ed in re#ulaton of e #enes ranscri$ton or ranslaton' +a is e mos likel! e$lanaton for e $osit &e associaton "eween e &arian allele and 2B2 '
Tis is a false $osit&e, due o $o$ulaton sratcaton "eween e case and conrol #rou$s #aered in eac sud!
.'
Te idented &arian is e functonal cause of e disorder
'
Te &arian is in linka#e disequili"rium wi a near"! #ene or oer sequence &ariaton in&ol&ed in e
etolo#! of e disorder Te &arian in e do$amine rans$orer does no a$$ear likel! o "e a functonal cause of e disorder "ecause neier allele a$$ears o in=uence e rans$orer act&i!' Te numerous sudies identf!in# a $osit&e associaton wi is allele su##es e ndin# is no a false $osit&e' Te mos likel! e$lanaton is a e &arian is in linka#e disequili"rium wi a near"! functonal can#e a increases e risk of 2B2 (see a$er 8)' Queston >4 18-!ear-old male $aten com$lains of a loss of cenral &ision in "o e!es' Te onse was less an 7 mons a#o and as $ro#ressed ra$idl!' Te $edi#ree !ou consruc of e $ro"ands famil! re&eals &ision loss in e $atens moer, all er &e si"lin#s, and e $ro"ands maernal #randmoer' ou de&elo$ a di*erental dia#nosis of likel! disorders a includes wic of e followin# '
.'
U% s!ndrome
'
Ue"ers erediar! neuro$a!
2'
Searns-%a!re s!ndrome
'
Uei#s s!ndrome
Ue"ers erediar! neuro$a! is a miocondrial disorder a leads o a ra$id onse of &ision loss' Te maernal ineriance $aFern is e rs clue a is $aten is likel! a*eced wi a miocondrial disease (see a$er 11)' Queston >3 ;n an e*or o identf! e in=uence of #enetc facors on "o insulin-de$enden (;22) and non-insulinde$enden (6;22) dia"ees mellius, researcers calculaed concordance raes for mono:!#otc ([) wins' oncordance raes of 30A50R a&e "een found for ;22' oncordance raes of C0R were o"ser&ed for 6;22' Ior "o !$es of dia"ees, di:!#otc (2[) concordance raes were 15R' +a does is informaton su##es concernin# e relat&e e*ec of #enetc and en&ironmenal facors for eac !$e of dia"ees '
6o conclusions can "e drawn from is sud!
.'
9enetc facors a&e liFle or no role in e etolo#! of ;22
'
6;22 is $rimaril! deermined "! non-#enetc facors
2'
9enetc in=uences eer a lar#er role in 6;22 an in ;22'
'
6;22 a$$ears o due o muatons in a sin#le, as !e unidented, #ene
Twin sudies are oNen used in an aFem$ o identf! e de#ree of #enetc in=uence eered on a disorder' ;f a disease were due solel! o #enes, concordance raes would a$$roac 100R for [ wins and 50R for 2[ wins' Te concordance raes are lower an ose &alues for is sud!, indicatn# a ere is also a role for non#enetc (en&ironmenal) facors in e etolo#! of 6;22 and ;22' Bowe&er, ere is a su"santal concordance for 6;22 amon# [ wins, su##estn# a #enetc facors $la! a $oentall! lar#er role in e etolo#! of is disorder (see a$er 15)' Queston >> Te .M "lood #rou$ is coordinaed "! ree alleles (, ., M) a e "lood #rou$ locus' Te and . alleles functon in a codominan manner, and "o are dominan o e M allele' Te followin# $edi#ree sows e "lood #rou$s from a ree-#eneraton famil!' .ased on is informaton, wa is e #eno!$e of icael a e .M "lood #rou$ locus '
MM
.'
.
'
M
2'
'
.M
icaels $arens a&e !$e "lood' Teir #eno!$es are eier or M' 2e$endin# on eir s$ecic #eno!$es, icael could eier "e , M or MM' icaels wife as !$e . "lood and is eier .. or .M a e "lood #rou$ locus' .ased on er moers !$e "lood, we can infer a icaels wife is .M a e .M locus A se ineris a . from er faer and an M from er moer' icael and is wife a&e ree cildren' Te rs cild as !$e "lood' icaels wife can $ass on an M or . allele o er cild' ;n order o a&e !$e "lood, e cild mus a&e ineried an M from is moer and an allele from icael' Te ird cild as !$e M "lood, wic can onl! occur wen an MM #eno!$e is $resen' %o icael mus also a&e an M allele' Ta means icael is M a e "lood #rou$ locus and as !$e "lood' Queston >5 +ic molecular $ro$er! "es distn#uises 26 from <6 '
26 conains a !dro!l #rou$ a e 4L $ositon of e ri"ose su#ar? <6 does no
.'
26 conains uracil? <6 su"stues adenine nucleotdes
'
26 is $resen in e c!o$lasm and nucleolus? <6 resides mainl! in e nucleus
2'
26 conains non-codin# sequences? ese are remo&ed durin# <6 $rocessin#
'
26 re$licaes in a conser&at&e manner? <6 re$licaton is semi-conser&at&e
26 conains se&eral sequences a are no $resen in $rocessed <6' %ome of ese sequences (suc as $romoer re#ions) are no ranscri"ed' Mer sequences (like inrons) are ranscri"ed, "u laer remo&ed durin# e $rocessin# se$s (see a$er 4)' Queston >7 er!l as $ol!c!stc kidne! disease (PS2), an auosomal dominan disorder' uaton anal!sis of er $ol!c!stn 4 #ene identes a 26 can#e a $re&ens e additon of a me!laed #uanine ca$ a e 5L end of e $ol!c!stn ranscri$' +a is e likel! e*ec of is can#e on e $ol!c!stn m<6 '
.ecause e $ol!() ail is normall! aFaced a e end of e 5L ca$, i canno "e added o e $ol!c!stn ranscri$
.'
Te inrons of e $ol!c!stn m<6 will no "e ecised, resultn# in im$ro$er or failed s$licin# of e ranscri$
'
Te $ol!c!stn m<6 will under#o $remaure de#radaton in e c!o$lasm, reducin# $roein le&els in e cell
2'
Te ri"osome will "e una"le o esa"lis e correc readin# frame, leadin# o incor$oraton of incorrec amino acids
'
Te Gca$less ranscri$ is u"iquitnaed "! e re$air maciner! of e cell, $re&entn# is rans$or ou of e nucleus
Te 5L ca$ is "elie&ed o $roec e ranscri$ from de#radaton "! cellular eonucleases' "sence of e ca$ leads o earl! de#radaton and a su"sequen reducton in $roein (see a$er 4)' Queston >H non! as a 26 can#e in e d!sro$in #ene a nucleotde $ositon >C7, wic corres$onds o e ird $ositon of e codon for amino acid 174' Tis can#e is classied as a silen muaton (i'e' i does no aler e ident! of amino acid 174)' Tis scenario illu sraes wic $rinci$le of e #enetc code '
Te code is de#enerae
.'
Te code is o&erla$$in#
'
Te code is uni&ersal
2'
Te code is non-o&erla$$in#
;n man! cases, more an one codon re$resens e same amino acid (e'#' and 9 "o code for $roline)' MNen, e ird $ositon of e codon can di*er wiou alerin# e corres$ondin# amino acid' .ecause of is $rinci$le, e #enetc code is said o "e de#enerae (see a$er 4)'
Queston >C 4-!ear-old #irl wi !$ercalcemia, su$ra&al&ular aortc senosis, sor saure and menal im$airmen is sus$eced of a&in# +illiams s!ndrome' sandard 9-"anded kar!o!$e re&eals no &isi"le a"normalites' Iluorescence in siu !"ridi:aton (I;%B) anal!sis is $erformed, usin# wo cromosome H $ro"esK one corres$onds o e cenromeric re#ion of e cromosome and e second is for e elastn #ene locaed a Hq11' ;n all e eamined cells of is #irl, wo si#nals are o"ained sowin# !"ridi:aton of e cromosome H cenromeric $ro"es' ;n conras, onl! one si#nal is o"ained for e locus-s$ecic elastn $ro"e, conrmin# e dia#nosis of +illiams s!ndrome' +a is e mos likel! #enetc cause of +illiams s!ndrome in is #irl '
6onsense muaton in e elastn #ene
.'
onosom! for cromosome H
'
IramesiN muaton in e elastn #ene
2'
icrodeleton of e elastn #ene
'
uaton in e elastn $romoer re#ion
Te I;%B resuls conrm a deleton in e Hq11 re#ion' 9i&en a no a"normali! was seen "! 9-"and anal!sis, e mos likel! cause of e s!ndrome is a microdeleton, oo small o "e seen on e sandard kar!o!$e (see a$er 3)' Queston >8 W$on kar!o!$e anal!sis, icael is found o "e >H,/' Te additonal cromosome likel! arose as a resul of wic of e followin# e&ens '
aernal nondisuncton a meiosis ;
.'
aernal nondisuncton a meiosis ;;
'
Paernal nondisuncton a meiosis ;
2'
Paernal nondisuncton a meiosis ;;
/ males likel! arise from a nondisuncton e&en durin# e second round of meiosis in s$ermao#enesis' .ecause ere are wo co$ies of e cromosome, e nondisuncton mus a&e occurred in e faer' 6ondisuncton a e second sa#e of meiosis resuls in e #amee recei&in# "o co$ies of one omolo# (in is case )' ;n conras, nondisuncton a meiosis ; $roduces a #amee wi one omolo# of eac cromosome $air (/) (see a$er 3)' Queston 50 +ic of e followin# cromosomal conditons would resul onl! in e $roducton of #amees a were eier nullisomic or disomic for cromosome 41 '
onosom! for cromosome 41
.'
10q41q reci$rocal ranslaton
'
$aracenric in&ersion for cromosome 41
2'
41q41q
;ndi&iduals in wom e q arms of e wo cromosomes 41 a&e fused are onl! ca$a"le of $roducin# #amees a are nullisomic (lackin# e ranslocaton) or disomic (conainin# e ranslocaton) for cromosome 41 (see a$er 3)'
Practce Tes 4 (1-50 questons) Queston 1 2ia#nostc estn# of $atens wi fra#ile / s!ndrome is $erformed "! di#estn# e sam$le 26 wi resricton en:!mes, fractonatn# e fra#mens "! si:e usin# #el elecro$oresis, denaurin# e fra#mens, ransferrin# em o a nirocellulose ler and !"ridi:in# e ler wi a radioact&el! la"eled nucleic acid $ro"e for e re#ion of ineres' Tis is a descri$ton of wic of e followin# ecniques '
Mli#onucleotde li#aton assa!
.'
%ouern "loZn#
'
%i:in# of $ol!merase cain reacton (P<) fra#mens
2'
%in#le-sranded conformatonal $ol!mor$ism (%%P)
'
26 microarra! anal!sis
Tis is an eam$le of a %ouern "lo (see a$er >)' Queston 4 !olo#ical ma$$in# ecniques allow a #ene o "e $!sicall! assi#ned o a cromosome or cromosome re#ion' +ic meod is mos likel! o "e used for is $ur$ose '
9-"andin# of mea$ase cromosomes
.'
Iluorescence in-siu !"ridi:aton (I;%B)
'
26 sequencin#
2'
on ra$$in#
I;%B allows i# resoluton ma$$in# of fra#mens a are se$araed "! 4A3 k" and u$ o H00 k" (see a$er 5)' Queston 3 Te %onic ed#eo# #ene (%BB) induces cell $roliferaton durin# em"r!onic de&elo$men in a i#l! re#ulaed manner' uatons or deletons in is #ene resul in wic of e followin# clinical feaures '
Wlnar-mammar! s!ndrome
.'
'
%!n$ol!dac!l!
2'
Bolo$rosence$al!
'
Birscs$run# disease
%BB muatons lead o olo$rosence$al!, e incom$lee se$araton of e de&elo$in# "rain ino distnc emis$eres and &enricles' Tere is oNen an a"sence of midline facial formaton, wic in se&ere cases ma! resul in e formaton of a sin#le, cenrall! locaed e!e (see a$er 7)' Queston > 3>-!ear-old woman is 10 weeks $re#nan' n ulrasound of er uerus identes an enlar#ed and $oorl! or#ani:ed $lacena, "u no feus is $resen' com$lee !datdiform mole is dia#nosed' +a ndin# would !ou e$ec from cromosome anal!sis and su"sequen 26 estn# of tssue from e com$lee mole '
78 cromosomes? 43 of $aernal ori#in and >7 of maernal ori#in
.'
>7 cromosomes, all of maernal ori#in
'
78 cromosomes? >7 of $aernal ori#in and 43 of maernal ori#in
2'
>7 cromosomes? 43 of $aernal ori#in and 43 of maernal ori#in
'
>7 cromosomes, all of $aernal ori#in
om$lee !datdiform moles a&e >7 cromosomes, all of wic are $aernal in ori#in' Tese moles, wic a&e a i# mali#nan $oental, are ou# o arise "! fertli:aton of an em$! e## (lackin# an! cromosomes) "! eier wo s$erm or "! a s$erm a under#oes re$licaton of is cromosomes "efore fertli:aton (see a$er 7)' Queston 5
%ara as emo$ilia , an /-linked recessi&e disorder, "u is oerwise clinicall! normal' 6eier er moer nor er faer as emo$ilia' uaton anal!sis of e famil!s facor /;;; #enes identes a nonsense muaton in one of e wo co$ies of e #ene in %aras moer' Tis same muaton was ransmiFed o %ara' 6o muatons are found in e facor /;;; #enes from %aras faer' Te co$! of e #ene ransmiFed o %ara from er faer also a$$ears o ar"or no muatons or 26 &arians' Sar!o!$e anal!sis of %ara is unremarka"le, wi no aneu$loid! or srucural a"normalites idented' .ased u$on ese ndin#s, wa is e mos likel! cause of %aras emo$ilia '
de no&o muaton on e $aernal co$! of e facor /;;; #ene
.'
%kewed / inact&aton in %ara
'
Bomo:!#osi! for an inact&atn# muaton in e facor /;;; #ene
2'
%ara as Turner s!ndrome
'
Te muaton on e maernal / cromosome is a dominan ne#at&e, causin# a #ain of functon a leads o emo$ilia'
%ara likel! as a skewed / inact&aton $role, wi mos cells inact&atn# e cromosome wi e normal co$! of e facor /;;; #ene' s a resul, e maori! of er cells can onl! ranscri"e e facor /;;; nonsense allele, leadin# o a &er! low le&el of facor /;;; "ein# $roduced and e clinical feaures of emo$ilia (see a$er H)' Queston 7 %e&en and %ara are married' Te! "o a&e acondro$lasia' ac alwa!s knew e! would onl! marr! someone wo also ad acondro$lasia' Tis !$e of coice, wic a e $o$ulaton le&el can disur" Bard!-+ein"er# equili"rium, is an eam$le of wic of e followin# '
9ene $oolin#
.'
Posit&e selecton
'
onsan#uini!
2'
ssorat&e matn#
'
%elect&e dominance
Mne of e assum$tons underl!in# Bard!-+ein"er# equili"rium is a random matn# occurs across e $o$ulaton' ssorat&e matn# is e endenc! for umans o coose $arners wo sare s$ecic caraceristcs' ;n is case, e caraceristc eends o a sin#le #ene rai (see a$er C)' Queston H %e&eral families wi wa a$$ears o "e an auosomal dominan disorder are recruied ino a #enetc linka#e sud! in an aFem$ o identf! e locaton of e causat&e #ene' Te researcers coordinatn# e sud! re$or a for e $ol!mor$ic marker 21C%>54, #i&en a recom"inaton fracton of 0, e UM2 score for ese families was @>'C5' .ased on is resul, wa can !ou conclude a"ou e locaton of marker 21C%>54 relat&e o e causat&e #ene under sud! '
arker 21C%>54 is on e same cromosome as e disease causin# #ene, "u far enou# awa! a recom"inaton occurs "eween e #ene and marker some $ro$orton of e tme'
.'
arker 21C%>54 is likel! locaed &er! close o e disease-causin# #ene and in ese families does no e$erience an! iner&enin# recom"inaton'
'
arker 21C%>54 sows some e&idence of "ein# near e disease-causin# #ene, "u additonal families need o "e recruied ino e sud! "efore linka#e can "e rml! esa"lised'
2'
arker 21C%>54 does no a$$ear o "e locaed an!were near e disease causin# #ene'
UM2 score of @3 or #reaer is su\cien for e&idence of linka#e "eween a marker and disease #ene' Queston C '
ult$le sudies of a #i&en disorder amon# si"lin#s a&e estmaed e eria"ili! of e disorder as equal o
0'C5' +a does is ndin# re&eal a"ou e cause of is disorder .'
Te maori! of e &ariance in e $eno!$e of is disease is caused "! #enetc in=uences
'
Tis disorder is likel! caused "! a sin#le #ene, wi no en&ironmenal in=uences
2'
n&ironmenal facors eer a #reaer in=uence o&er disease likeliood an #enetc facors
Beria"ili! is a measure of e oal &ariance in a rai $eno!$e a is caused "! addit&e #enetc facors' Beria"ili! is measured on a scale from 0 o 1 and e i#er e &ariance, e #reaer e role of #enetc facors (see a$er 8)' Queston 8 n associaton sud! is underaken o in&est#ae e $ossi"le link "eween !$erension and a s$ecic allele &arian (ins555-570) of e #ene' +a queston will is sud! aFem$ o answer '
2oes !$erension occur more oNen an e$eced in eended famil! mem"ers wen one mem"er as e ins555-570 allele
.'
Bow muc recom"inaton occurs around e #ene amon# indi&iduals wi !$erension and e ins555570 allele
'
;s e ins555-570 allele sared "eween a*eced relat&es more oNen an e$eced "! cance
2'
2oes e frequenc! of ins555-570 di*er "eween $o$ulatons wi and wiou !$erension
ssociaton sudies com$are e frequenc! of a $artcular allele in $o$ulatons wi and wiou e disease of ineres' ;f e allele is in&ol&ed in e etolo#! of e disorder, i would "e e$eced o occur wi #reaer frequenc! amon# e a*eced $o$ulaton' Queston 10 sin#le nucleotde can#e in e #ene for "ea #lo"in su"stues e amino acid &aline for #luamic acid a e si $ositon' Tis can#e a*ecs e solu"ili! of e resultn# $roein under cerain conditons' +a is e corres$ondin# disorder '
B!dro$s fealis
.'
Berediar! $ersisence of feal emo#lo"in
'
2ela "ea alassemia
2'
oole!s anemia
'
%ickle cell disease
%ickle cell disease is caused "! e &aline o #luamic acid can#e in "ea #lo"in (see a$er 10)' Queston 11
Mne
.'
Two
'
Tree
2'
Iour
'
Ii&e
B" B disease resuls from e deleton of ree of e four al$a #lo"in #enes' small amoun of al$a #lo"in is $roduced "! e remainin# #ene, leadin# o e $resence of a small le&el of normal B" ' Tere is an o&erwelmin# maori! of "ea #lo"in, resultn# in e $roducton of e "ea #lo"in eramer, B" B' Te $resence of is eramer leads o e clinical s!m$oms of B" B disease (see a$er 10)' Queston 14 %orl! aNer "ir, elissa is dia#nosed wi $en!lkeonuria (PSW), an auosomal recessi&e disorder' +a is e e*ec of PSW causin# muatons '
;m$air e a"ili! of cells o de#rade li$ids, leadin# o oici!
.'
'
2isru$ e functon of e en:!me !rosinase
2'
Uead o !$er$en!lalaninemia, wic dama#es e "rain and 6%
'
Pre&en e rans$or of sodium and cloride ions across e mem"rane of cells
Te muaton for PSW is in e #ene for $en!lalanine !dro!lase (PB), wic is res$onsi"le for con&ertn# $en!lalanine o !rosine' .locka#e of is $awa! leads o a "uildu$ of $en!lalanine, wic dama#es e de&elo$men of e 6% and inerferes wi "rain functon (see a$er 11)' Queston 13 5-!ear-old is idented wi menal im$airmen, dislocaton of e lenses, cur&aure of e s$ine, $ecus eca&aum and aracnodac!l!' ;ncreased le&els of omoc!stne are idented in is urine' +ic of e followin# #enes is mos likel! o conain e causat&e muaton for is cild '
Ii"rillin
.'
olla#en !$e ;
'
.ranced cain keoacid decar"o!lase (.S2)
2'
!saionine "ea s!nease
'
onnein >3
;ncreased le&els of omoc!stne is e allmark of omoc!stnuria, mos oNen caused "! a decienc! of c!saionine "ea s!nease' ; is oNen confused wi arfan s!ndrome due o an o&erla$ in some s!m$oms, "u ele&aed omoc!stne is no a feaure of arfan s!ndrome (see a$er 11)' Queston 1> +ic en:!me is mos likel! decien in indi&iduals wi a muco$ol!saccaridosis disorder '
n en:!me in e urea c!cle leadin# o !$erammonemia
.'
U!sosomal en:!mes in&ol&ed in macromolecule de#radaton
'
Ui&er en:!mes necessar! o de#rade #l!co#en o release #lucose
2'
n:!mes a clea&e s$in#oli$ids
'
n en:!me necessar! for e mea"olism of monosaccarides suc as frucose
uco$ol!saccaridosis disorders are l!sosomal sora#e diseases (see a$er 11)' Queston 15 $armaceutcal com$an! carries ou a doseAres$onse es for a new dru# A 300 indi&iduals are #i&en a sandard dose of e dru# and are esed 1 laer o deermine e amoun of e dru# circulatn# in e "loodsream' Te concenratons of e dru# amon# e indi&iduals are sown ere' %uc a ndin# su##ess wa a"ou e mea"olism of e dru# in queston '
9enetc in&ol&emen in e mea"olism $rocess is minimal
.'
Te mea"olic $rocess is $ol!#enic
'
Tree #enes mea"oli:e e dru#
2'
sin#le #ene mea"oli:es e dru#
'
ea"olism occurs in a codominan manner "! e en:!mes from wo #enes
rimodal discontnuous res$onse su##ess mea"olism is under e conrol of a sin#le #ene wi e ree res$onses corres$ondin# o e ree #eno!$es a is #eneK omo:!#ous dominan, eero:!#ous, omo:!#ous recessi&e (see a$er 14)' Queston 17 ;n cancer, loss of eero:!#osi! amon# umor cells su##ess a e re#ion Glos ma! conain wic #ene !$e '
umor su$$ressor
.'
rece$or for a #row facor
'
n onco#ene
2'
cell c!cle kinase
'
c!o$lasmic !rosine kinase
MNen, loss of eero:!#osi! indicaes e locaton of a $uat&e umor su$$ressor' Te rs co$! of e muaton is usuall! ineried' Te second muaton occurs rou# a mecanism a remo&es a $arenal allele]oNen miotc nondisuncton, #ene deleton, #ene con&ersion followin# 26 re$air, ec' (see a$er 1>)' Queston 1H ;ndi&iduals wi Ui-Iraumeni s!ndrome a&e an increased risk of de&elo$in# a lar#e num"er of cancers a relat&el! earl! a#es' uatons in wic #enes are res$onsi"le for is disorder '
<.1
.'
T$53
'
c-
2'
S;T
'
<%
T$53 is a umor su$$ressor #ene' ; is e mos frequenl! muaed #ene idented o dae' ;ndi&iduals wi UiIraumeni s!ndrome ineri a muaton in one of e wo co$ies of e #ene' Te oer muaton is acquired somatcall! in a s$ecic tssue, leadin# o e cancer' Queston 1C +a mecanism causes mos cases of Turner s!ndrome (>5,/) '
Pos-:!#otc loss of a se cromosome, leadin# o mosaicism
.'
deleton of e lon# arm of e / cromosome aNer fertli:aton
'
Te formaton of a rin# cromosome durin# maernal meiosis
2'
Uoss of a se cromosome rou# $aernal meiosis
'
;socromosome formaton for e / cromosome durin# maernal meiosis
Turner s!ndrome arises in C0R of all cases rou# a $aernal nondisuncton e&en, wic resuls in a s$erm a lacks a se cromosome' Queston 18 artn as con#enial "ilaeral a"sence of e &as deferens (.E2), leadin# o serili!' 26 anal!sis carried ou as $ar of a fertli! sud! identes muatons in "o co$ies of artns c!stc "rosis ransmem"rane conducance re#ulaor (IT<) #ene' artn does no a&e $ancreatc insu\cienc!, nor does e a&e a isor! of recurren lun# infectons or $ulmonar! in&ol&emen' Te een o wic IT< act&i! is reduced "! muaton correlaes well wi e clinical $eno!$e of e disorder' +ic of e followin# le&els of IT< act&i! would mos likel! "e found amon# artns cells '
1R
.'
7R
'
10R
2'
45R
'
50R
Ue&els of IT< act&i! "eween CR and 14R are associaed wi e mildes c!stc "rosis $eno!$e, .E2 (see a$er 18)' Queston 40 screenin# es for c!stc "rosis as "een esa"lised and daa #aered on e rs !ears ndin#s' Te screen correcl! identes one undred and nine! (180) indi&iduals wi c!stc "rosis' 5000 indi&iduals recei&e a $osit&e screenin# resul, "u dia#nostc sudies sow a e! do no, in fac, a&e c!stc "rosis? 10 indi&iduals
recei&e a ne#at&e screenin# resul, "u acuall! do a&e c!stc "rosis' n additonal >85,000 indi&iduals recei&e a ne#at&e screenin# resul and do no a&e c!stc "rosis' +a is e s$ecici! of is screenin# es '
88R
.'
85R
'
10R
2'
5R
'
1R
%$ecici! descri"es e $ro$orton of una*eced indi&iduals wo are idented "! a screen as una*eced' ; is a measure of ow well e es deecs indi&iduals wo are rul! a*eced, com$ared wi ose indi&iduals wo es screen $osit&e, "u are also una*eced' ;n e eam$le a"o&e, 5000 indi&iduals are Gfalse $osit&e A e! recei&e a $osit&e screen es, "u do no a&e c!stc "rosis' %$ecici! is calculaed as e $ercena#e of screen-ne#at&e, disease-ne#at&e indi&iduals di&ided "! e oal num"er of disease-ne#at&e indi&iduals >85,000D(5000 @ >85,000) 88R (see a$er 40)' Queston 41 screenin# es for $en!lkeonuria (PSW) identes >C indi&iduals as Gscreen $osit&e wo are dia#nostcall! conrmed o a&e PSW' n additonal 7000 Gscreen-$osit&e indi&iduals are found o "e una*eced "! furer dia#nostc estn#' Two additonal indi&iduals wi PSW recei&ed Gscreen-ne#at&e scores' 18>,000 indi&iduals recei&ed a ne#at&e screenin# resul and are no a*eced wi PSW' +a is e sensit&i! of is screenin# meod '
88R
.'
8CR
'
8HR
2'
87R
'
>CR
%ensit&i! is deermined "! identf!in# e $ro$orton of rul! a*eced indi&iduals idented "! e screen' ;n is eam$le, >C of ou 50 a*eced indi&iduals recei&ed a $osit&e screenin# resul >CD50 87R (see a$er 40)' Queston 44 nia is a*eced "! a rare auosomal dominan disorder a occurs amon# males and females wi an equal frequenc!' Ior e&er! 100 indi&iduals wo ineri a muaton in e disease #ene, onl! 50 $resen wi clinical s!m$oms of is disorder' nia as a dau#er, arol' ssumin# a neier nias us"and nor arols us"and carries e muaton, wa is e $ro"a"ili! a arols rs cild will ei"i e clinical s!m$oms of e disease '
3D>
.'
1D4
'
1D>
2'
1DC
'
1D17
Tere is a 1D4 cance a nia will $ass alon# e muaton o arol and a 1D4 cance a arol will $ass alon# e muaton o er cild' ;f arols cild recei&es e muaton, ere is a 1D4 cance e or se will acuall! sow clinical s!m$oms' Taken o#eer, is #i&es a 1DC oal $ro"a"ili!' Queston 43 $aten wi a famil! isor! of "reas cancer comes o !ou seekin# ad&ice a"ou #enetc estn#' ou $ro&ide er wi informaton relaed o o$tons, coss, limis of iner$reaton, ec' %e asks !ou Gsould ; #e e es ou ell er a i is entrel! er decision o make' +a is e eical $rinci$le rele&an in is case
'
.enecence
.'
uonom!
'
ondentali!
2'
Justce
'
6onmalecence
uonom! refers o e ri# of e $aten o "e in car#e and make is or er own decisions, a leas o e een a is $ossi"le #i&en e circumsances' Queston 4> leN li$ and $alae is a multfacorial rai wi a frequenc! in aucasians of 1D1000' "ou 70AC0R of a*eced indi&iduals are males' 9i&en is informaton, wic saemen "es descri"es recurrence risk in is $o$ulaton '
Te recurrence risk for e sons of an a*eced male is equal o e recurrence risk for is dau#ers
.'
Te recurrence risk for a si"lin# of an a*eced siser is smaller an e recurrence risk for a si"lin# of an a*eced "roer
'
Te recurrence risk for cildren of an a*eced male is less an e recurrence risk for cildren of an a*eced female
ccordin# o e conce$s oulined in e lia"ili!Dresold model, if e conditon is more common amon# indi&iduals of one #ender, e relat&es of an a*eced indi&idual of e more frequenl! a*eced se will "e a lower risk an e relat&es of an a*eced indi&idual of e less frequenl! a*eced se (see a$er 8)' Queston 45
0
.'
1D>
'
1D4
2'
3D>
'
1
lou# Buntn#ons disease can "e esed for direcl!,
rra!-"ased com$arat&e #enome !"ridi:aton (a9B)
.'
icroarra! #ene e$ression anal!sis
'
2'
6orern "loZn#
'
%erial anal!sis of #ene e$ression (%9)
icroarra! #ene e$ression anal!sis utli:es mult$le !"ridi:aton assa!s o measure e relat&e a"undance of ousands of #ene ranscri$s simulaneousl!' Queston 4H aron, an C-!ear-old of skena:i Jewis ancesr!, $resens wi anemia, "one and oin $ain, e$aome#al! and s$lenome#al!' Be is dia#nosed wi 9aucer disease, a li$id sora#e disorder a resuls from e accumulaton of #l!cos!lceramide' +a is e "es o$ton o mana#e arons disorder '
9ene era$!
.'
Ui&er rans$lan
'
n:!me re$lacemen era$!
2'
Palliat&e care
lou# inital aFem$s a en:!me re$lacemen era$! sowed liFle success, sli# modicaton o e en:!me ar#es i o macro$a#e l!sosomes, leadin# o dramatc alle&iaton of s!m$oms in a*eced indi&iduals (see a$er 11)' Queston 4C an! disorders are no caused "! sin#le #ene i neriance, "u are multfacorial' ;n counselin# siuatons in&ol&in# ese disorders, ow are recurrence risks idented '
%in#le #ene ineriance risks are mult$lied "! a multfacorial fracton, cosen o re$resen e conri"uton from oer #enetc facors $lus e en&ironmenal in=uence
.'
.a!es eorem is a$$lied, usin# modicatons of e G$rior risk calculaton utli:ed amon# sin#le-#ene defecs
'
Te risks are deermined em$iricall!, "ased on $re&ious o"ser&atons of disease recurrence amon# acual families
2'
;n e siuaton descri"ed a"o&e, i is usuall! necessar! o em$lo! em$iric risks o $ro&ide recurrence informaton' Tese are "ased on e o"ser&ed recurrence amon# families sudied o dae' Queston 48 ara is a 3C-!ear-old woman in er 17 week of $re#nanc!' %e is referred for amniocenesis on e "asis of ad&anced maernal a#e' Te amniotc sam$le recei&ed "! e c!o#enetcs la" is s$li ino ree se$arae aliquos and cell culures are esa"lised from eac aliquo' Te resultn# kar!o!$es are sown "elow' K Sar!o!$e found in ei# cells from culure 3' .K Sar!o!$e found in e remainin# cells of culure 3 and amon# all cells eamined from culures 1 and 4' s e la" direcor, !ou need o assess e risk for mosaicism in e feus' +a will !ou re$or '
Eiruall! 0R
.'
40R
'
50R
2'
C0R
'
100R
Tis is an eam$le of a le&el 4 mosaicism for risom! 41 in a male feus' ;n a le&el 4 mosaicism, wo or more cells in
onl! one culure a&e an alernae kar!o!$e' Tis is mos likel! a culure artfac, "u em$iric sudies a&e sown a ere is u$ o a 40R cance e mosaicism is real and will "e idented in e feus' Iollow-u$ feal "lood sam$lin# is sometmes used in an aFem$ o resol&e ese !$es of ndin#s' Queston 30 icael is e #randson of a woman a*eced wi Buntn#ons disease' Be as asked o under#o #enetc estn# o deermine weer e is likel! o de&elo$ Buntn#ons' Bed like more informaton a"ou is #enetc es' ou ell im a e dia#nostc es for Buntn#ons disease s$ecicall! measures wa '
Te $resence and amoun of e untn#tn $roein
.'
Te $resence of deletons s$annin# one or more eons of e untn#tn #ene
'
Te num"er of $ol!#luamine residues in e 3L WT< of e untn#tn #ene
2'
Te num"er of 9 re$eas in e 5L re#ion of e untn#tn #ene
'
Te $resence of sin#le-"ase can#es in e codin# re#ion of e untn#tn #ene
6earl! all indi&iduals wi Buntn#ons disease a&e an e$ansion of a 9 $ol!#luamine re$ea in e 5L re#ion of e untn#tn #ene' 2ia#nostc ess measure e si:e of e 9 re$ea racK allele si:es of >0 or more 9 re$eas are in&aria"l! associaed wi e disease (see a$er 18)' Queston 31 li:a"e and
Parenal #onadal mosaicism
.'
;nde$enden de-no&o muatons in a*eced cildren
'
;ncom$lee $eneraton
2'
n&ironmenal e$osure limied o a*eced cildren
'
45R recurrence risk for eac cild
6I1 is an auosomal dominan, com$leel! $eneran disorder' lou# a"ou 1D4 of all cases are due o new muatons, mult$le a*eced cildren from una*eced eal! $arens are more likel! due o $arenal #onadal mosaicism, were a $ro$orton of e #amees from one $aren carr! e 6 I1 muaton (see a$er 18)' Queston 34 Po$ulaton screenin# for carriers of c!stc "rosis is now commonl! o*ered o all $re#nan women' ;f e woman is found o carr! a muaton in IT<, se is in&ied o "rin# in er $arner for estn#' ;f e $arner is also a carrier, $renaal dia#nosis is en o*ered' +a is is screenin# a$$roac called '
ascade screenin#
.'
ou$le screenin#
'
Iamil! screenin#
2'
Tar#eed screenin#
'
Two-se$ screenin#
Tis is a descri$ton of wo-se$ screenin#K rs e moer is esed and if $osit&e, estn# is o*ered o e faer (see a$er 40)' Queston 33 n infan #irl was "orn wi se&ere !$oonia and lack of s$onaneous mo&emen' Te #irls moer remem"ered feal mo&emens were "o fain and s$oradic durin# $re#nanc!' ontnued $ro#ression of muscle weakness a*eced "o swallowin# and res$iraor! functon, leadin# o dea a 1C mons' 9enetc estn# idented a deleton a cromosome 5q13, encom$assin# "o e sur&i&al moor neurone #ene and e neuronal a$o$osis ini"ior! $roein #ene' +a is e mos likel! dia#nosis for is disorder
'
2ucenne muscular d!sro$!
.'
Ju&enile Parkinsons disease
'
m!oro$ic laeral sclerosis
2'
%$inal muscular aro$! (%)
'
!oonic d!sro$!
Tis is a descri$ton of % !$e ;' Te disease is caraceri:ed "! de#eneraton of e anerior orn cells of e s$inal cord leadin# o $ro#ressi&e muscle weakness (see a$er 18)' Queston 3> 2a&id and %ara a&e four cildren' Mne as sor saure, de&elo$menal dela! and "ilaeral radial a$lasia (an u$$er lim" a"normali! a in&ol&es e radius)' Tis cild was "orn wiou um"s and laer de&elo$ed "one marrow failure, leadin# o reduced le&els of all "lood cell !$es' n eaminaton of culured cells from is cild re&ealed mult$le cromosomal "reaks' +ic cromosomal "reaka#e s!ndrome is mos consisen wi is clinical descri$ton '
Ianconi anemia
.'
.looms s!ndrome
'
aia elan#iecasia
2'
/eroderma $i#menosa
'
;I s!ndrome
Tis is a descri$ton of Ianconi anemia, an auosomal recessi&e disorder caraceri:ed a e c!o#enetc le&el "! cromosome "reaka#e and #a$s' Te associaton wi u$$er lim" a"normalites is unique amon# e cromosomal "reaka#e s!ndromes (see a$er 1C)' Queston 35 2urin# $renaal ulrasound, an amniotc "and is disco&ered o encircle e leN and of e feus' "ir, due o e consricton of e amniotc "and, se&eral of e n#ers on e infans leN and are missin# and e remainder are $oorl! formed' +a is e erm descri"in# e mecanism a led o is sin#le con#enial a"normali! '
%equence
.'
2!s$lasia
'
2eformaton
2'
alformaton
'
2isru$ton
disru$ton occurs wen some ouside facor (usuall! no #enetc) disru$s e normal de&elo$menal $awa! (see a$er 17)' Queston 37 n#ie, a 47-!ear-old woman, as "een akin# a medicine $rescri"ed "! er docor o rea se&ere acne' Te act &e in#redien in is medicaton is retnoic acid' +ile akin# e medicaton, n#ie "ecomes $re#nan' %e #i&es "ir o a son wo is a*eced wi !droce$al!, cleN $alae and low-se deformed ears' Tese malformatons can "e raced o e e*ec of e retnoic acid' ;n is eam$le, retnoic acid is a(n)K '
imera
.'
Beerokar!on
'
nancer
2'
Terao#en
'
or$o#en
Tis is a classic eam$le of a erao#en A an a#en a causes "ir defecs "! a*ectn# em"r!onic or feal
de&elo$men (see a$er 17)' Queston 3H +ic ndin# would su##es a en&ironmenal facors $la! a maor role in e etolo#! of essental !$erension '
i#ran $o$ulatons sow no can#e in disease $re&alence
.'
Te correlaton for "lood $ressure "eween ado$t&e cildren and eir "iolo#ical $arens is lower an e correlaton for cildren wo remain wi eir "iolo#ical $arens'
'
Two !$erensi&e #rou$s eis, one wi normal and one wi ele&aed s!solic $ressures
2'
'
;ncidence of !$erension is increased in identcal wins com$ared o non-identcal wins
;f a disorder is dri&en in lar#e $ar "! en&ironmenal facors, ado$ed cildren would sow lower correlatons wi eir "iolo#ical $arens (wo do no sare eir en&ironmen) an would cildren wo sa! wi (and us sare e en&ironmen of) "iolo#ical $arens (see a$er 15)' Queston 3C mil! is an 1C-!ear-old wo as recenl! "een dia#nosed wi cronic m!eloid leukemia' romosome anal!sis of er wie "lood cells would re&eal wic a"normali! '
(8?44)(q3>?q11)
.'
del(1H$13'1)
'
(C?1>)(q4>?q34)
2'
2ou"le minue for 6
'
del(13q)
Te GPiladel$ia cromosome, o"ser&ed in 80R of indi&iduals wi is form of leukemia, is e $roduc of a reci$rocal ranslocaton "eween e lon# arms of cromosomes 44 and 8 (see a$er 1>)' Queston 38 Te Gmserdam crieria (a leas ree a*eced relat&es, a leas wo successi&e #eneratons a*eced, cancer dia#nosed "efore a#e 50 in a leas one relat&e) is used o selec i#-risk indi&iduals for wa form of ineried cancer '
.reas cancer
.'
M&arian cancer
'
olorecal cancer
2'
T!roid cancer
'
Ui-Iraumeni s!ndrome
Te mserdam crieria are used o identf! indi&iduals a i# es risk of colorecal cancer (see a$er 1>)' Queston >0 Te mea"olism of a cerain dru# is measured usin# a doseAres$onse es in 1000 indi&iduals' ll indi&iduals were #i&en a sandard dose and aNer 30 minues, e concenraton of e dru# circulatn# in e "lood was measured'
+en $loFed,
e
o&erall
concenratons
formed e followin# disri"uton' +a acton is e mea"olism of is dru# mos likel! conrolled "! '
sin#le dominan #ene
.'
sin#le recessi&e #ene
'
ult$le #enes
2'
anno "e deermined wi e a&aila"le daa
unimodal disri"uton su##ess a e mea"olism is under e conrol of mult$le #enes (i'e' e mea"olism is $ol!#enic, see a$er 14)' Queston >1 ndrew, a >-!ear-old male, as wie air, wie skin a does no an, and "lue, full! ranslucen irises' Be also $resens wi $oor &isual acui! and n!sa#mus' Tese s!m$oms are likel! o "e caused "! a decienc! in wic one of e followin# en:!mes '
Ierrocelaase
.'
Beosaminidase-
'
r#inase
2'
T!rosinase
'
41-!dro!lase
ndrew $resens wi e s!m$oms of !$e ; oculocuaneous al"inism (M)' ;ndi&iduals wi M !$e 1 a&e deciencies in !rosinase, leadin# o e a"sence of melanin $i#menaton (see a$er 11)' Queston >4 &el!n is a 7-da!-old new"orn "rou# o e emer#enc! room "! er $arens' lou# se a$$eared normal a "ir, er $arens re$or se as no "een feedin# well, as "ecome di\cul o rouse and is now a&in# sei:ures' &el!n as a low core em$eraure, cere"ral edema and as sli$$ed ino a coma' %e is dia#nosed wi orniine ranscar"am!lase decienc!' nal!sis of &el!ns "lood will mos likel! sow an ele&aton of wic mea"olic $roduc '
Wric acid
.'
mmonia
'
Iolae
2'
Wrea
'
Pen!lalanine
Mrniine ranscar"am!lase decienc! is an in"orn error of e urea c!cle' ; leads o an accumulaton of ammonia wic is oic o e ner&ous s!sem (see a$er 11)' Queston >3 arcus and armen a&e a cild wi am"i#uous eernal #enialia' Te inernal #enialia are female and cromosome anal!sis is >7,//' .iocemical sudies re&eal a decienc! of 41-!dro!lase' +a is e mos likel! dia#nosis A.
Congenital adrenal hyperplasia
.'
Pom$es disease
'
ndro#en insensit&i!
2'
Burlers s!ndrome
'
am$omelic d!s$lasia
on#enial adrenal !$er$lasia is e resul of muatons in 41-!dro!lase' ; is e mos common cause of am"i#uous #enialia in females (see a$er 11)' Queston >> i#uels famil! as familial !$ercoleserolemia (IB) and is a increased risk of earl! coronar! arer! disease' Bi# coleserol le&els in $ersons wi IB are due o defect&e or decien low-densi! li$o$roein rece$ors' +en screenin# indi&iduals in is famil!, wa earl! clinical si#n will !ou look for '
$$earance of a Gcerr!-red retnal s$o
.'
Birsutsm
'
Iormaton of Bein: "odies in e red "lood cells
2'
n ele&aton of serum creatne
'
Iormaton of mult$le anomas
anoma is a su"cuaneous de$osi of li$id' ; oNen a$$ears durin# cildood or adolescence in indi&iduals wi IB (see a$er 11)' Queston >5 aria is a 43-!ear-old woman wo as recenl! notced loss of coordinaton, and di\cul! in s$eakin# and swallowin#' Ber $arens a&e also notced sar$ $ersonali! can#es in aria' W$on clinical eaminaton, aria is noed o a&e a Sa!ser-Ileiscer rin# a e corneal mar#in of er e!es' .ased u$on arias s!m$oms, wa disorder sould "e sron#l! considered '
a$le s!ru$ urine disease
.'
Pro$ionic acidemia
'
+ilsons disease
2'
crdles disease
'
9alacosemia
+ilsons disease is a disorder of co$$er mea"olism' ; oNen causes "o neurolo#ical and "ea&ioral can#es in a*eced indi&iduals and is reco#ni:ed "! e $resence of a Sa!ser-Ileiscer rin# in e e!e (see a$er 11)' Queston >7
llelic eero#enei!
.'
Pleioro$!
'
Penerance
2'
Uocus eero#enei!
'
ntci$aton
muaton a a*ecs numerous or#an or tssue !$es is sai d o ei"i $leioro$! (see a$er H)' Queston >H ikklos is a 8-mon-old "o! of 9reek ori#in wo $resens wi se&ere anemia, #row reardaton and e$aos$lenome#al!' Bemo#lo"in elecro$oresis on cellulose aceae ($B C'>) #i&es e followin# resuls' +ic disorder is mos consisen wi is clinical $role '
.ea alassemia
.'
%ickle cell disease
'
B!dro$s fealis
2'
eemo#lo"inemia
'
B"B disease
.ea alassemia resuls from e a"sence of functonal "ea #lo"in (and e consequen a"sence of B"), leadin# o e s!m$oms descri"ed a"o&e' ;n #eneral, ese feaures do no a$$ear untl a few mons aNer "ir "ecause #amma #lo"in is e maor non-al$a #lo"in cain durin# feal de&elo$men and earl! $osnaal life' .ecause e #amma and dela #lo"in cains are inac, B"4 and B"I $roducton contnues (see a$er 10)' Queston >C Te $edi#ree sown ere follows e ineriance of e facor E Ueiden muaton, wic increases e risk of rom"o$ilia' Pen# is omo:!#ous for e muaton' 9i&en e informaton sown in is $edi#ree, wa is e cance a e rs"orn cild of Jin (Pen#s son) will also "e omo:!#ous for e facor E Ueiden muaton
'
Eiruall! 0R
.'
45R
'
50R
2'
H5R
'
100R
Jin is eero:!#ous for e muaton, as is is wife' Te $ro"a"ili! a e! "o $ass e muaton on o a cild is erefore 45R' Queston >8 Sirsen is a 5-!ear-old #irl wi aaia and sei:ures' Te resul of an a$$arenl! normal $re#nanc! and "ir, Sirsen $ro#ressed normall! untl e middle of er second !ear, wen se "e#an losin# s$eec and moor skills' Tere was a marked deceleraton in e #row of er ead durin# is same $eriod' .! 4> mons, se ad de&elo$ed a $aFern of and wrin#in#, "u ad los e use of er ands for oer $ur$oses and ad se&ere im$airmen in e$ressi&e and rece$t&e lan#ua#e' .ased u$on ese ndin#s, Sirsen would "e mos likel! o "e a*eced wi wic disorder '
2i9eor#e s!ndrome
.'
dward s!ndrome
'
iller-2ieker s!ndrome
2'
'
Paau s!ndrome
00 $ol!$s' .enamins moer and a maernal uncle died of cancer "efore e a#e of 55' .enamin also as con#enial !$erro$! of e retnal $i#men e$ielium' 9i&en is se of clinical ndin#s, in wic #ene is .enamin mos likel! o a&e a muaton '
.<4
.'
UB1
'
P
2'
TP53
'
<T
uatons in "o co$ies of e P #ene are a allmark of familial adenomaous $ol!$osis (IP), an auosomal dominan disorder accountn# for a$$roimael! 1R of colorecal cancer' ; is caraceri:ed "! undreds o ousands of adenomaous $ol!$s rou#ou e colon' on#enial !$erro$! of e retnal $i#men e$ielium ($i#mened areas of e retna) is a ndin# oNen associaed wi IP (see a$er 1>)'
Queston 1 ;n areas were Plasmodium falci$arum malaria occurs, carriers of sickle cell anemia a&e #reaer resisance o infecton, com$ared wi indi&iduals wo a&e wo normal co$ies of e "ea #lo"in #ene' +en carriers red "lood cells are in&aded "! e malaria $arasie, e cells sickle and are desro!ed' ;n ese $o$ulatons, Bard!+ein"er# equili"rium is disur"ed for e "ea #lo"in muaton' Tis disur"ance of #enetc ineriance in $o$ulatons is referred o as wa '
llelic di*usion
.'
6e#at&e selecton
'
ssorat&e matn#
2'
Beero:!#oe ad&ana#e
'
9enetc driN
Beero:!#oe ad&ana#e is an eam$le of $osit&e selecton, were e $resence of one co$! of e sickle cell muaton increases e ness of e indi&idual (see a$er C)' Queston 4 mon# e Mld Mrder mis in e W%, llis-&an re&eld s!ndrome, an auosomal recessi&e disorder, is $resen a a muc i#er frequenc! an a o"ser&ed amon# oer #rou$s of uro$ean descen' +ic of e followin# facors, cou$led wi e social and reli#ious isolaton of is $o$ulaton, mos likel! accouns for is ele&aed frequenc! '
founder e*ec amon# e mis $o$ulaton
.'
reduced muaton rae amon# e mis
'
2'
;ncreased re$roduct&e ness of e a*eced males amon# e mis
'
n en&ironmenal risk facor $resen a increased frequenc! amon# e mis
Te mos likel! e$lanaton for is o"ser&aton is a one or wo of e ori#inal founders of e Mld Mrder mis were carriers for e llis-&an re&eld muaton' 2ue o e resriced num"er of marria#e $arners a&aila"le o mem"ers of is #rou$, e frequenc! of e muaton increased o a relat&el! i# frequenc!, resultn# in an increase in e num"er of marria#es "eween wo carriers and a su"sequen increase in disease frequenc! (see a$er C)' Queston 3
;n=ammaor! $eri$eral neuro$a!
.'
arco-arie-Too disease
'
6euro"romaosis
2'
.ecker muscular d!sro$!
'
Uei# disease
arco-arie Too disease, caraceri:ed "! cronic moor and sensor! $ol!neuro$a!, is mos oNen caused "! increased dosa#e of PP44 as a resul of a du$licaton of e cromosome 1H #ene (see a$er 18)'
Queston > nne-li:a"e is a*eced wi a rare form of retnits $i#menosa (a $ro#ressi&e retnal de#eneraton)' Tis form of e disease onl! occurs wen indi&iduals are eero:!#ous for muatons in wo di*eren unlinked #enes,
Pleioro$!
.'
o-dominan ineriance
'
2i#enic ineriance
2'
Triallelic ineriance
'
9enetc eero#enei!
2i#enic ineriance descri"es a siuaton were e addit&e e*ecs of eero:!#ous muatons a wo di*eren #enes leads o e occurrence of a disorder' ; is eori:ed a e indi&idual e*ec of eac muaton is no su\cien "! iself o cause e disorder, "u e oin $resence crosses some resold of cell dama#e or inur!, leadin# o s!m$oms (see a$er H)' Queston 5 ;n s$erm, mos meiotc recom"inaton "eween e / and cromosomes occurs in e $seudoauosomal re#ion'
// indi&iduals wi am"i#uous #enialia
.'
/ indi&iduals wo are $eno!$icall! female and are fertle
'
// indi&iduals wo are $eno!$icall! female, "u infertle
2'
/ indi&iduals wo are $eno!$icall! male, "u infertle
'
// indi&iduals wo are $eno!$icall! male, "u infertle
Te %< #ene is e $rimar! facor a deermines maleness' %< e$ression ri##ers a series of downsream #ene act&aton, leadin# o e formaton of masculine inernal and eernal #enialia' Translocaton of %< ono e / cromosome resuls in // males' Bowe&er, man! of e #enes a conrol s$erm de&elo$men and fertli! reside on e cromosome, and // males wo lack ese #enes are erefore infertle (see a$er 7)' Queston 7 Te followin# $edi#ree sows !our $aten, arsa, wo is a*eced wi a sin#le-#ene, auosomal dominan disorder a sows C0R $enerance, and er wo cildren, icael and arcus' icael is also clinicall! a*eced wi e disorder' Te $ro"a"ili! a arcus will a&e e clinical si#ns associaed wi e disorder is closes o wic of e followin# coices '
40R
.'
>0R
'
50R
2'
C0R
'
100R
arsas di:!#otc wins arose from e fertli:aton of wo ooc!es "! wo s$erm' Te! are #enetcall! equi&alen o si"lin#s, sarin# 50R of e #enes in common on a&era#e' Te a*ecton saus of icael and arcus are inde$enden' Tere is a 50R a arsa $assed alon# e muaton o arcus' ;f arcus recei&ed e muaton, ere is an C0R cance a e will de&elo$ e clinical s!m$oms of e disorder' s a resul, ere is a >0R o&erall cance a arcus will sow si#ns of e disease (see a$er 5)'
Queston H Te
followin#
sequence
is
found
in
e
$romoer
re#ion
of
e
insulin
#eneK
5L-
T9T9T999TT99TT9TT999-3L +ic of e su"ses of is sequence sown "elow re$resen e mos likel! ar#e re#ion for reco#niton and clea&a#e "! a resricton endonuclease '
T
.'
9T99
'
99T
2'
TT9
'
99
)' Queston C Te $ol!merase cain reacton (P<) is a $owerful ool and is commonl! used for dia#nostc sudies' Bowe&er, use of e P< is limied "! wic of e followin# e$erimenal conditons '
4>A>C ours is required o com$lee e assa!
.'
Uar#e amouns of sartn# 26 are needed
'
ult$le re#ions of 26 canno "e coam$lied in e same reacton
2'
onaminatn# 26 can readil! "e coam$lied
Te P< is a &er! ro"us $rocess a will am$lif! an! 26 fra#men $resen in a sam$le a is omolo#ous o e forward and re&erse $rimers used in e reacton' Te $rocess is $rone o am$lif! conaminatn# 26? for is reason, P< is carried ou under sric #uidelines in areas free of conaminatn# sequence (see a$er >)' Queston 8 our $aten, $raim, is sus$eced of a&in# oseo#enesis im$erfeca' ou seek molecular conrmaton of is dia#nosis' Te es !ou wan $erformed in&ol&es se#menal am$licaton of e $romoer and eonic re#ions of "o colla#en !$e ; #enes' Te resultn# dou"le-sranded $roducs are denaured and one of e srands is su"eced o #el elecro$oresis, lookin# for &ariatons from e normal elecro$oretc mo"ili! of a fra#men' +ic of e followin# la"oraor! ess will !ou order '
%in#le srand conformatonal $ol!mor$ism (%%P)
.'
26 microarra! for resequencin# $ur$oses
'
2enaurin# i#-$erformance liquid cromao#ra$! (2BPU)
2'
'
Mli#onucleotde li#aton assa! (MU)
%%P' %in#le sranded 26 fra#mens assume a s$ecic ree-dimensional srucure "ased, in $ar, on eir s$ecic 26 sequence (see a$er >)' Queston 10 our $aten, 6iru$ama, is 17 weeks $re#nan' Wlrasound of e feus sowed an increase in e nucal ickness, wic is oNen associaed wi risom! 41' ou order an amniocenesis, and "o !ou and !our $aten are anious for a ra$id dia#nosis' Mrderin# wic c!o#enetc anal!sis resuls in e fases clinical re$or '
Bi#-resoluton 9iemsa "andin#
.'
Iluorescen in-siu !"ridi:aton (I;%B)
'
2'
Ilow c!omer!
'
I;%B can "e used o eamine iner$ase cells (as well as mea$ase cells) wi a urnaround tme as ra$id as 4> ours (see a$er 3)'
Queston 11 Paro!smal kinesi#enic d!skinesia (PS2) is a rare
auosomal
caraceri:ed
"!
dominan e$isodic
disorder
coreiform
or
d!sonic mo&emens a are "rou# on or eacer"aed
"!
&olunar!
mo&emen'
#enome-wide linka#e sud! was conduced usin#
a
lar#e
frican-merican
kindred
se#re#atn# e PS2 $eno!$e in an aFem$ o identf! e mos likel! locaton of e PS2 #ene (.enneF U., (1)K145A130)' Te wo-$oin UM2 scores from a $orton of markers alon# cromosome 17 are sown ere' Te descendin# order in e a"le corres$onds o eir $!sical order (from cenromere o elomere) on e q arm of e cromosome' +a conclusions can reasona"l! "e drawn from ese daa Ta"le 1K Two $oin UM2 scores for cromosome 17 loci and PS2' '
217%>18 is conained wiin e #ene "oundaries of e $uat&e PS2 locus
.'
Te sron#es e&idence for linka#e o e PS2 locus is found a marker 217%H78
'
Te allele of marker 217%>18 a was co-ineried wi e clinical $eno!$e is e PS2-causin# muaton
2'
Te $!sical locaton of e PS2 #ene is likel! found "eween markers 217%H53 and 217%>18
UM2 scores of 3'0 or #reaer, wi corres$ondin#l! small recom"inaton fractons, are acce$ed as si#nican e&idence for linka#e wi a s$ecic marker' ;n is eam$le, markers 217%H53, 217%3387 and 217%>18 acie&e is le&el' ; is likel! e locaton of e PS2 #ene will "e found somewere in is iner&al' Queston 14
Eiruall! 0R
.'
$$roimael! 45R
'
$$roimael! 3CR
2'
$$roimael! 50R
'
$$roimael! H5R
denin# caraceristc of miocondrial 26 is ineriance rou# onl! e maernal linea#e' %$erm miocondria are #enerall! desro!ed so a all miocondria are deri&ed from e moer' onsequenl!, none of e o*s$rin# of a male carr!in# a miocondrial muaton will ineri e muaton (see a$er 4)' Queston 13 nna-arie is a*eced wi "ea-alassemia' olecular dia#nosis of er "ea-#lo"in #enes identes a muaton a remo&es e 100 nucleotdes immediael! $recedin# e sar sie for ranscri$ton' +a "ea-#lo"in re#ulaor! elemen is remo&ed "! is deleton '
Pol!aden!laton si#nal
.'
TT "o
'
3L inronDeon "oundar! for inron 4
2'
3L WT< (unranslaed re#ion)
'
Terminaton codon
%equences immediael! u$sream of e ranscri$ton sar sie #enerall! conain conser&ed sequences im$oran for e initaton of ranscri$ton' Tese include e TT "o (a$$roimael! 45 "ase $airs u$sream of e ranscri$ton sar sie) and e 9 and T "oes (usuall! wiin e C0 "ase $airs u$sream of e sar sie) (see a$er 4)' Queston 1> a!-lin as !$e 1 oseo#enesis im$erfeca (M;)' %own "elow is er 26 sequence for a $orton of eon 7 for e colla#en !$e 1 #ene, wic conains e muaton res$onsi"le for !$e 1 M;' Te corres$ondin# normal sequence is also sown' a!-linK 5L TTTTT9T A 3L 6ormalK 5L ATTTTT9T A 3L a!-lin as wa !$e of muaton '
6onsense
.'
issense
'
%u"stuton
2'
;nserton
'
IramesiN
Tis is an eam$le of a framesiN muaton' sin#le "ase deleton as disru$ed e readin# frame for ranslaton (see a$er 4)' Queston 15 &ann is a*eced "! oseo#enesis im$erfeca (M;), an auosomal dominan disorder resultn# from defect&e !$e ; colla#en' lou# &anns M; is caused "! a loss of functon muaton in e $ro al$a ; #ene, onl! one muaton is needed o $roduce e clinical e*ecs of M;' Tis case illusraes wic of e followin# #enetc conce$s '
Beero#enei!
.'
Ba$loinsu\cienc!
'
Bomo$lasm!
2'
B!$ermor$
'
Beero$lasm!
Ba$loinsu\cienc! descri"es e siuaton were 1D4 of e normal le&els of e #ene $roduc leads o $eno!$ic e*ecs (see a$er 4)' Queston 17 Bemo#lo"in $roein elecro$oresis was used o deermine weer 100 indi&iduals carried #enes for normal emo#lo"in (B") or e Ue$ore &arian (B"U)' Quantat&e anal!sis of e elecro$oresis resuls is sown "elow' B"DB" 70R? B"DB"U 30R? B"UDB"U 10R? +a is e allele frequenc! of B" in is sam$le '
0'34
.'
0'57
'
0'70
2'
0'7C
'
0'H5
mon# is sam$le of 100 indi&iduals, ere are 400 cromosomes' Mf ose 400, 150 are B" (140 from e B" omo:!#oes $lus 30 conri"ued "! e B"DB"U eero:!#oes)' Te frequenc! of B" is erefore 150D400 0'H5' Queston 1H
&an is a 4C-!ear-old man wi a !oun#er "roer wo died from !$e 4 9aucer disease, an auosomal recessi&e l!sosomal sora#e disorder a is faal "! e a#e of 4 !ears' +a is e $ro"a"ili! a &an is a eero:!#ous carrier for e 9aucer muaton '
0'45
.'
0'33
'
0'50
2'
0'7H
'
0'H5
&ans $arens were eac carriers of e 9aucer muaton' "ir, 1D> of eir o*s$rin# will ineri wo normal co$ies of e corres$ondin# #ene, 1D4 will ineri one co$! of e normal #ene and one co$! of e muaton, and 1D> will ineri "o co$ies of e muaton (and a&e 9aucer disease)' Bowe&er, as &an is 4C !ears old, e canno $ossi"l! "e a*eced wi 9aucer disease, "ecause ese indi&iduals die "efore e a#e of 4 !ears' Ta lea&es ree equall! likel! $ossi"ilitesK 1) e ineried "o normal co$ies from is $arens, 4) e ineried a muaton from is moer and a normal co$! from is faer, and 3) e ineried a normal co$! from is moer and a muaton from is faer' Two of ese ree would resul in a eero:!#ous carrier for e muaton, #i&in# &an a 4D3 $ro"a"ili!' Queston 1C %ara is a known eero:!#ous carrier of a muaton a causes ma$le s!ru$ urine disease (%W2), an auosomal recessi&e disorder a resuls in e ina"ili! o mea"oli:e "ranced cain amino acids' Te frequenc! of is muaton in e $o$ulaton is ne#li#i"le' %e as wo dau#ers wo eac a&e one cild' +a are e cances a "o %aras #randcildren a&e ineried a co$! of e %W2 muaton '
1D34
.'
1D17
'
1D>
2'
3DC
'
1D4
Tere is a 1D4 cance a %ara $asses alon# e muaton o one of er dau#ers, followed "! a 1D4 cance a e dau#er in urn $asses e muaton alon# o er cild' %o ere is a 1D> cance a one #randcild will "e a carrier for e %W2 muaton' ;n e same wa!, ere is a 1D> cance a e oer #randcild will carr! e %W2 muaton' Te cance a "o #randcildren will carr! e muaton is 1D> 1D> 1 D17' Queston 18
1D514
.'
1D457
'
1D14C
2'
1D7>
'
1D34
s emocromaosis is an auosomal recessi&e disorder, e #rea #randfaer of
carriers' Tere is a 1D4 cance a ) and en eac $ass e muaton o a cild (wic would occur on a&era#e 1D> of e tme)' Taken o#eer, e $ro"a"ili! of is occurrin# is 1D7> 1D> 1D457' Queston 40 sus$ec in a ra$e and assaul case as "een #eno!$ed a ree inde$enden microsaellie re$ea markers' Be is a aucasian of uro$ean descen' Bis alleles a ese ree markers mac e alleles reco&ered from e male fracton of e ra$e ki colleced from e &ictm sorl! aNer e aFack' Te sus$ec is omo:!#ous for e rs wo microsaellies eamined and eero:!#ous for e ird' Te macin# allele frequencies amon# e #eneral aucasian $o$ulaton are 0'50 for e rs microsaellie and 0'40 for e second microsaellie' Te macin# allele frequencies for "o alleles of e ird microsaellie are 0'40 and 0'10' +a is e $ro"a"ili! a a random indi&idual drawn from e aucasian $o$ulaton would mac e alleles $resen on e male fracton o"ained from e ra$e ki '
0'0004
.'
0'000>
'
0'0010
2'
0'0017
'
0'0040
Te $ro"a"ili! is deermined "! mult$l!in# o#eer e frequencies of e ree #eno!$es $resen on e ra$e ki' Te #eno!$e frequencies are deermined usin# e Bard!-+ein"er# equaton' Te #eno!$e frequenc! of eac omo:!#ous microsaellie is $_, so e #eno!$e frequenc! for e rs microsaellie is 0'50_ 0'45' %imilarl!, e #eno!$e frequenc! for e omo:!#oe a e second microsaellie is 0'40_ 0'0>' Te frequenc! for e eero:!#ous #eno!$e a e ird microsaellie is 4$q, or 4 0'40 0'10 0'0>' ult$l!in# e ree #eno!$e frequencies o#eer #i&es us e $ro"a"ili! a a randoml! cosen indi&idual in e aucasian $o$ulaton would a&e e same #eno!$es as ose idented on e ra$e ki, 0'45 0'0> 0'0> 0'000>' Queston 41 Belene as wo "roers wi .ecker muscular d!sro$!' %e marries 9ar!, wo also as .ecker muscular d!sro$!' Belene as us #i&en "ir o a dau#er' +a is e $ro"a"ili! a is cild will "e a*eced wi .ecker muscular d!sro$! '
Eiruall! 0
B.
1/4
'
1D4
2'
3D>
'
1
s "o Belenes "roers a&e .ecker muscular d!sro$! (an /-linked recessi&e disorder), i is likel! a one of er $arens carried e muaton' Belene as a 1D4 cance of "ein# a carrier' ;f Belene carries e muaton, ere is a 1D4 cance se will $ass i o a cild' %o ere is a 1D4 1D4 1D> cance a a cild will ineri a maernal co$! of e muaton' 9ar! will $ass e muaton for .ecker o all is dau#ers' Ior a female o "e a*eced wi .ecker muscular d!sro$!, se mus ineri a muaton from "o er faer and er moer' ;n e siuaton descri"ed a"o&e, ere is a 1D> cance e new"orn dau#er of Belene and 9ar! will ineri wo muatons and "e a*eced'
Queston 44 ris and is "roer Todd "o a&e 2ucenne muscular d!sro$!' Tere is a maernal famil! isor! of is disorder' Jean, e "o!s maernal aun, is ineresed in "e#innin# a famil!' +a is e $ro"a"ili! a se is a eero:!#ous carrier of e disease #ene '
Eiruall! 0
.'
1DC
'
1D>
2'
3DC
'
1D4
Te moer of ris and Todd is an o"li#ae carrier, wic means a one of er $arens mos likel! carried e muaton res$onsi"le for 2ucenne muscular d!sro$!' Tere is a 1D4 cance a e muaton was $assed o er siser as well' Queston 43 onsider e $edi#ree sown ere, were an auosomal
dominan
disorder
is
"ein#
ransmiFed' four allele marker as "een #eno!$ed and e corres$ondin# alleles are sown "elow e s!m"ol for eac indi&idual' +a is e recom"inaton frequenc! for e marker and disease locus '
0
.'
1DC
'
3DC
2'
1D4
'
5DC
Te #eno!$es of e indi&iduals in #eneraton ; esa"lis e linka#e $ase for indi&idual ;;-1' Wnder e !$oesis of linka#e "eween e disease and e #eno!$ed marker, is man would ineri e disease causin# muaton, carried on e same cromosome as allele 3, from is faer (indi&idual ;-1)' Be would ineri e normal co$! of e #ene, carried on e same cromosome as allele 5, from is moer (indi&idual ;-4)' .ased on ese a$lo!$es, and ose of is una*eced mae (indi&idual ;;-4), we would $redic a e cildren wo ineri e G3 allele from eir faer would also "e a*eced, wile ose a ineri e G5 allele would no' Tis is e case for all "u one of e o*s$rin# (;;;-H)' Tis indi&idual would "e ermed a recom"inan' Tus, ere are se&en nonrecom"inans and one recom"inan amon# e o*s$rin#' Mne recom"inan in ei# meiotc e&ens !ields a recom"inan fracton of 1DC' Queston 4> c!o#enetcs la"oraor! re$ors a kar!o!$e of >7,//,del(5)$15 for nia and a kar!o!$e of >7,//,du$(5)$15 for ar#are' .ased on is informaton alone, ow se&ere would !ou e$ec nias clinical $eno!$e o "e com$ared o ar#ares clinical $eno!$e '
ore se&ere an ar#are
.'
Uess se&ere an ar#are
'
"ou e same se&eri! as ar#are
2'
;m$ossi"le o ell from e informaton a&aila"le
;n #eneral, a loss of #enetc maerial $roduces more se&ere consequences an a #ain of #enetc maerial' .ased onl! on is informaton, !ou would e$ec e deleton $aten (nia) o "e more se&erel! a*eced an a
du$licaton $aten (ar#are)' Queston 45 Te $edi#ree of e Pael famil! is sown ere' %aded indi&iduals are a*eced wi oseo#enesis im$erfeca (M;), an auosomal dominan disorder' uatons a is locus a&e a $enerance of 80R' four allele microsaellie, linked o e M; locus a a recom"inaton fracton of 0'00, as "een !$ed for all mem"ers of e famil!' Te accom$an!in# #eno!$es are sown in e elecro$oresis ima#e "elow e $edi#ree' .ased on ese #eno!$es wa is e a$$roimae risk a indi&idual H will a&e e clinical s!m$oms of M; '
Eiruall! 0R
.'
10R
'
50R
2'
80R
'
100R
.ecause ere is no recom"inaton "eween e M; locus and e !$ed microsaellie, we can use e alleles of e microsaellie o $redic e a*ecton saus of e famil! mem"ers' Te M; causin# muaton is on e same cromosome as allele 4 in e a*eced faer' Tis allele was ineried "! indi&iduals 3 and 7, wo are "o a*eced wi M;' ;ndi&idual H, wo ineried allele > from is faer, will "e una*eced' Queston 47 onsider cromosomes 1 and 4 a e "e#innin# of meiosis' romosome 1 omolo#s are la"eled a e cenromeres as ,a' romosome 4 omolo#s are la"eled a e cenromeres as .,"' ;f a e tme of fertli:aton, a maure ooc!e conained e cenromeres la"eled and ., wic com"inaton would "e found in e second $olar "od! '
a and "
.'
and "
'
a and .
2'
and .
2urin# e rs meiotc di&ision, omolo#ous cromosomes are se$araed' is $oin, a and " would "e found in e rs $olar "od! and and . would remain in e ooc!e' e second meiotc di&ision, siser cromatds are se$araed' Te second $olar "od! would conain siser cromatds a are identcal o ose a remain in e maure ooc!e (see a$er 3)' Queston 4H ree-allele locus on e / cromosome conrols e #reen-sensit&e $i#men for color &ision' Te normal allele G9 is dominan o e oer wo alleles, "o of wic are muatons' Te #1 muaton leads o a conditon called G#reen siN A e $resence of a weakened #reen-sensit&e $i#men were onl! cerain sades of #reen are indistn#uisa"le from "rowns' Te #1 muaton is dominan o e #4 muaton, wic resuls in G#reen "lindness, were reds, #reens and !ellows canno "e distn#uised' man wi normal &ision marries a woman wi #reen "lindness' +a !$e of #reen &ision will e sons "orn o is cou$le a&e '
ll will a&e normal #reen &ision
.'
1D4 wi a&e normal &ision? 1D4 will a&e #reen siN
'
ll will a&e #reen siN
2'
1D4 will a&e #reen siN? 1D4 will a&e #reen "lindness
'
ll will a&e #reen "lindness
Ior /-linked disorders, ere is no conri"uton from e faer (wo $ro&ides e cromosome insead)' ll sons
will recei&e one of e moers wo / cromosomes' ;n is case, "o of e moers / cromosome carr! e #4 muaton, so all sons will a&e one #4 allele and a cromosome' Tis com"inaton will resul in #reen "lindness' Queston 4C 2ecreasin# $roducton of wic form of emo#lo"in would eoretcall! "ene a $aten wi "ea alassemia maor '
Ieal B"
.'
.ea #lo"in
'
l$a #lo"in
2'
9amma #lo"in
;ndi&iduals a*eced wi "ea alassemia maor $roduce liFle o no "ea #lo"in' Tis resuls in an o&era"undance of al$a #lo"in su"unis, leadin# o e formaton of al$a su"uni eramers' Tese insolu"le eramers are armful o red "lood cells and lead o eir $remaure desructon' 2ecreasin# e le&els of al$a #lo"in would eoretcall! reduce e formaton of al$a eramers (see a$er 10)' Queston 48 +ic of e followin# kar!o!$es would mos likel! "e $resen amon# maure, normal, uman s$erm '
4>,
.'
44,/
'
43,
2'
>7,/
'
>7,//
aure uman #amees a&e 43 cromosomes' %$erm will a&e eier an / or se cromosome, "u no "o (see a$er 3)' Queston 30 onique, a 45-!ear-old woman, as us #i&en "ir o a dau#er wi se&ere de&elo$menal a"normalites' Te infan as microce$al!, "ilaeral cleN li$ and $alae, micro$almia wi "ilaeral colo"omas, low-se ears and a &enricular se$al defec' Te infans ands and fee a$$ear normal' Te infan dies 10 da!s aNer "ir' romosome sudies of is infan would likel! re&eal wic of e followin# kar!o!$es '
>5,//, der(13?41)(q10Kq10)
.'
>H,//, @1C
'
>5,/M
2'
>H,//, @13
'
>7,//, A15q11'4 Aq13
Te a"o&e $!sical descri$ton is consisen wi a dia#nosis of risom! 13 (see a$er 1C)' Queston 31 Wnlike al$a alassemia, wic is oNen identa"le in uero, "ea alassemia usuall! $resens onl! aNer "ir' Tis is "ecauseK '
Ieal emo#lo"in is su\cien o mee o!#en needs $renaall!
.'
;n uero, all o!#en requiremens are $ro&ided "! maernal red "lood cells
'
2ela emo#lo"in eramers rans$or o!#en durin# feal de&elo$men
2'
Prenaall!, al$a-#lo"in eramers are ca$a"le of su$$l!in# o!#en o e feus
'
m"r!onic emo#lo"in, $resen untl us aNer "ir, mees feal o!#en requiremens
Ieal emo#lo"in, com$osed of al$a and #amma su"unis, is e $rimar! emo#lo"in $resen durin# de&elo$men' round e tme of "ir, #amma e$ression is diminised as "ea #lo"in e$ression is increased'
;ndi&iduals wi muatons a im$air "ea #lo"in $roducton "e#in o sow s!m$oms as e $ro$orton of feal emo#lo"in dro$s wiou a concomian rise in adul (al$a, "ea) emo#lo"in (see a$er 10)' Queston 34 n auosomal recessi&e disorder as a frequenc! of 1 $er 4500 in e aucasian $o$ulaton' ll known cases of is disorder resul from an identcal muaton in e causat&e #ene' $$roimael! wa $ercena#e of is $o$ulaton as wo co$ies of e normal allele for is #ene '
$$roimael! 4R
.'
$$roimael! >R
'
$$roimael! 80R
2'
$$roimael! 87R
'
$$roimael! 8CR
ccordin# o Bard!-+ein"er# equili"ria, e frequenc! of e disease allele (q) is e square roo of e frequenc! of e disease (1D4500), wic is 1D50' %ince e frequenc! of e disease allele $lus e frequenc! of e normal allele mus equal 1, e frequenc! of e normal allele ($) is >8D50' Te frequenc! of e omo:!#ous normal #eno!$e is ($)($) $_ (>8D50)_ 4>01D4500 O 87R' Queston 33 nne, a !oun# woman from e WS, as a cild wi c!stc "rosis' %e di&orces er us"and and marries le, a #enetcall! unrelaed man from Irance' %udies a&e sown a e frequenc! of c!stc "rosis amon# indi&i duals of 6orern uro$ean descen is 1D4500' +a is e risk a nne and le will a&e a cild wi c!stc "rosis '
1D4500
.'
1D450
'
1D100
2'
1D45
'
1D>
!stc "rosis is an auosomal recessi&e disorder' s nne as an a*eced cild, se is erself a carrier for a muaton a causes c!stc "rosis' ccordin# o Bard!-+ein"er# equili"rium, if e disease frequenc! is 1D4500 (q_), e frequenc! of e disease allele is q 1D50' Te cance a le is a carrier for c!stc "rosis is 4$q O 4q 1D45' ;f le as e muaton, e cance e would $ass i alon# o is cild is 1D4' Tere is a 1D4 cance nne will $ass alon# er muaed allele o er ne cild' PuZn# is all o#eer #i&es a risk of 1D45 1D4 1D4 1D100' Queston 3> 0s' Te screenin# es deecs a*eced indi&iduals wi a 8CR sensit&i! and a 5R false $osit&e rae'
80R
.'
85R
'
8H'5R
2'
8CR
'
88R
.efore e screenin# es, ere was an a $riori risk of 50R a
wo does no imself a&e I, as recenl! married and would like o sar a famil!, "u is concerned a"ou e risk of $assin# I o is cildren' 26 sam$les are no a&aila"le from is "roer or from is $arens, wo are "o deceased' Be under#oes 26 estn# for e H0 mos common IT< muatons A a $anel a deecs 80R of e muatons found amon# indi&iduals of norern uro$ean descen' Be ess ne#at&e for all H0 muatons' 9i&en is informaton, wa is e $ro"a"ili! a e is a eero:!#ous carrier for I '
4D3
.'
1D>
'
1D7
2'
1D15
'
1D45
.e#in wi e $rior risk a Uee&i is a carrier for I' .ecause e is no a*eced wi e disorder, e risk e is a carrier is 4D3' Ten use .a!esian anal!sis o calculae e risk #i&en is ne#at&e estn# resuls, is new risk of "ein# a carrier for I is 1D7' %o, #i&en a e esed ne#at&e for e I $anel, is new risk of "ein# a carrier for I is 1D7' Queston 37
romosome ranslocaton
.'
Wni$arenal disom!
'
romosome du$licaton
2'
6ucleotde su"stuton
'
uosomal monosom!
Wni$arenal disom! (e ineriance of wo cromosomes from one $aren) occurs in a$$roimael! 30R of Prader-+illi cases' Te wo cromosomes 15 are ineried maernall!' Queston 3H an! cases of iller-2ieker s!ndrome are caused "! microdeletons wiin e re#ion of e U;%1 #ene, locaed a 1H$13'3' +ic dia#nostc ecnique would mos likel! deec a H5 kilo"ase deleton in is #ene re#ion '
26 sequencin#
.'
%andard 9-"andin#
'
Iluorescen in-siu !"ridi:aton (I;%B)
2'
2enaurin# i# $erformance liquid cromao#ra$! (2BPU)
I;%B is e "es ecnique for e case descri"ed' Te microdeleton is oo small o "e idented "! sandard 9"andin#' Te muaton is oo lar#e o "e deeced usin# sandard 26 sequencin# or 2BPU meods ] e normal co$! of e U;%1 #ene would "e am$lied and screened, maskin# e $resence of e deleton' Te di*erence in #ene dosa#e a e U; %1 #ene could, owe&er, also "e idented usin# a quantat&e a$$roac suc as quantat&e P<' Queston 3C %e&en is a 4>-our-old, full-erm, infan wo is !$oonic, lear#ic and as sallow, ra$id "reain#' Bis moer #a&e "ir 4 !ears a#o o a son wi similar s!m$oms wo died H4 ours aNer "ir' +a es sould "e ordered
on %e&en rs '
romosome anal!sis
.'
Plasma ammonia le&el
'
%wea cloride le&el
2'
Plasma $en!lalanine le&el
'
Bemo#lo"in elecro$oresis
%e&en as e s!m$oms of a urea c!cle disorder, wic leads o a "uild-u$ of ammonia, wic reaces e "rain and can cause irre&ersi"le dama#e and dea' le&aed ammonia le&els are a allmark of urea c!cle disorders' Queston 38 nondisuncton e&en for cromosome 4 occurs durin# e rs meiotc di&ision of a $rimar! s$ermaoc!e' e end of meiosis wa would e $ro$ortons "e of normal, disomic, and nullisomic #amees '
ll disomic #amees
.'
ore disomic an nullisomic #amees
'
qual num"er of disomic and nullisomic #amees
2'
4K1K1 rato of normal, disomic and nullisomic #amees
'
1K1K4 rato of normal, disomic and nullisomic #amees
Te rs meiotc di&ision se$araes omolo#ous cromosomes' 6ondisuncton a is sa#e resuls in wo #amees wi era cromosomes and wo #amees wi missin# cromosomes (see a$er 3)' Queston >0 Te followin# $edi#ree sows e ransmission of a &er! rare disorder' +ic indi&idual in e $edi#ree is an o"li#ae carrier for e muan allele of e disease-causin# #ene '
nn
.'
.e
'
Jim
2'
ike
'
%allie
Tis re$resens a disorder wi an /-linked recessi&e ineriance $aFern' %allie, wo #i&es "ir o a son wi e disorder, and a dau#er wo is a carrier, is an o"li#ae carrier' %ci:o$renia is a $s!cotc illness caraceri:ed "! disor#ani:ed ou#, alered "ea&ior and a decline in social functonin#' +a ndin# su##ess e de&elo$men of sci:o$renia is, a leas in $ar, #enetcall! in=uenced '
Te lifetme risk o de&elo$ sci:o$renia is 1R for an indi&idual in e #eneral $o$ulaton and rises o >R if e associaed sci:oid $ersonali! disorder is also considered
.'
Te incidence of sci:o$renia is increased amon# "iolo#ical relat&es of sci:o$renic ado$ees com$ared o e "iolo#ical relat&es of conrol ado$ees
'
Te concordance rae for mono:!#otc wins wi sci:o$renia is 15R, wic is equal o e concordance rae for di:!#otc wins
2'
Te com$arison of "ir mon o incidence of sci:o$renia re&eals an ecess of winer "irs amon# indi&iduals wi sci:o$renia
'
Te concordance rae for sci:o$renia for identcal wins "orn o a sci:o$renic $aren is i#er if e wins are reared o#eer raer an reared se$arael!
;ncreased incidence amon# "iolo#ical relat&es $ro&ides su$$or for #enetc facors in e etolo#! of sci:o$renia (see a$er 15)' Queston >4 ndrew is eero:!#ous for "o e facor E Ueiden muaton, wic renders e facor E resisan o clea&a#e,
and e $rorom"in &arian 940410, wic increases $rorom"in le&els' +a disease is e is a an increased risk of de&elo$in# '
Bemo$ilia
.'
oronar! arer! disease
'
Eenous rom"osis
2'
B!$erension
'
Talassemia
;ndi&iduall!, e facor E Ueiden muaton and $rorom"in &arian "o increase e risk of dee$ &ein rom"osis four- or &efold' ;neried o#eer, e! confer a wen!fold increase in risk (see a$er 15)' Queston >3 Mne of e #enes in&ol&ed in codeine mea"olism is P427, a com$onen of e c!ocrome P->50 famil!' Tis en:!me mediaes M-deme!laton of codeine o $roduce mor$ine' Tere are o&er C0 distnc alleles idented for is #ene' an! alleles (classied as Gnormal alleles) do no aler en:!me act&i! le&els' Mer alleles inact&ae P427 act&i! (G$oor mea"oli:er alleles)' small num"er of indi&iduals a&e P427 #enes were a #ene du$licaton e&en as creaed an adacen, full! functonal era co$! of e P427 #ene (Gulrara$id alleles)' 74-!ear-old man wi "ilaeral $neumonia as a cou# a does no res$ond o o&er-e-couner medicaton' Be is #i&en sandard dosa#e of oral codeine o relie&e e cou#' few da!s ino reamen, e $aten "ecomes unres$onsi&e and de&elo$s a life-reaenin# mor$ine inoicaton' Tis $aten mos likel! $ossesses wic of e followin# P427 allele com"inatons '
6ormalDnormal
.'
6ormalD$oor mea"oli:er
'
Poor mea"oli:erDulrara$id
2'
6ormalDulrara$id
;ndi&iduals wi ulrara$id P427 act&i! can $roduce #reaer amouns of mor$ine from codeine and as a resul, ma! e$erience ea##eraed clinical consequences in res$onse o sandard doses' Tis is es$eciall! likel! wen e oer P427 allele is eier normal or also ulrara$id' ;f e oer allele is a $oor mea"oli:er, e o&erall mea"olic e*ec will a$$ear as if ere are wo normal alleles $resen (see a$er 14)' Queston >> an! cases of andro#en insensit&i! s!ndrome are caused "! deletons wiin e andro#en rece$or #ene locaed on e / cromosome' +a dia#nostc ecnique would mos likel! deec a H00 "ase $air deleton a com$leel! remo&es eon C in is #ene '
%ouern "loZn#
.'
26 sequencin#
'
500 "and kar!o!$e
2'
Iluorescen in-siu !"ridi:aton (I;%B)
'
n C00 "and kar!o!$e
%ouern "los are mos likel! o deec is relat&el! small deleton' Te deleton is cerainl! oo small o deec "! kar!o!$e, and &er! likel! oo small for I;%B deecton as well' Mn e oer and, a deleton of is si:e is oo lar#e for deecton "! sandard sequencin# ecniques' Queston >5 ;ndi&iduals wi erediar! non-$ol!$osis colorecal cancer (B6P) oNen a&e muatons in wa class of #enes '
$o$osis $awa!
.'
ismac re$air
'
%i#nal ransducton
2'
ell adesion
B6P is due o muatons in a series of $roofreadin# #enes in&ol&ed in e re$air of 26 mismaces a arise due o errors in 26 re$licaton (see a$er 1>)' Queston >7 Te U6 #ene on cromosome 1 encodes lamin $roein, a ke! com$onen of e nuclear mem"rane' sin#le $oin muaton in is #ene is res$onsi"le for e maori! of cases of Bucinson-9ilford $ro#eria, an eremel! rare, auosomal dominan, $remaure a#in# s!ndrome' os cases are caused "! a silen "ase su"stuton, wic act&aes a cr!$tc s$lice-sie donor in e las eon of e #ene a is 150 nucleotdes 5L of e raditonal 9T donor sie' +a is e mos likel! e*ec of is muaton '
Te nal 50 amino acids are deleed from e end of e $roein
.'
di*eren amino acid is insered in e $roein a e sie of e muaton
'
Te entre las eon is s$liced ou of e ranscri$ durin# $rocessin#
2'
Te lamin #ene is ranscri"ed a a reduced rae, decreasin# $roein le&els
ct&aton of a cr!$tc s$lice-sie donor creaes a new locaton for e eonDinron "oundar!' +en e ranscri$ under#oes $rocessin#, e las eon is s$liced a is locaton, resultn# in e loss of e nal 150 nucleotdes' onsequenl!, e $roein will "e 50 amino acids sorer' Queston >H lassic
9-"andin# and P4-s$ecic =uorescen in-siu !"ridi:aton (I;%B)
.'
2enaurin# i#-$erformance liquid cromao#ra$! (2BPU) screenin# and 26 sequencin#
'
9-"andin# and quantat&e P<
2'
26 sequencin# and %ouern "loZn#
'
Quantat&e P< and %ouern "loZn#
26 sequencin# or 2BPU-"ased screenin# will identf! e $oin muatons, "u canno deec e microdeletons (e non-deleed co$! of e #ene will am$lif! and $ro&ide normal sequence)' %ouern "loZn#, I;%B or quantat&e P< will identf! e microdeletons, wic are oo small o "e deeced "! a sandard 9-"anded kar!o!$e' Queston >C ;n a$$roimael! >R of all cases of 2own s!ndrome, e additonal cromosomal maerial is e resul of a ' +en a ranslocaton 2own s!ndrome case is idented, e cromosomes of e $arens are also eamined o deermine weer eier $aren is a "alanced carrier of e ranslocaton' ;f one of e $arens is idented as carr!in# e ranslocaton, ow does e #ender of e carrier a*ec recurrence risks for additonal cildren wi 2own s!ndrome '
.'
'
