CHROMOSOME DISORDER 2.doc

7/23/2019 CHROMOSOME DISORDER 2.doc

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CHROMOSOME DISORDER

Alterations of the chromosomes (numerical and structural) occur in about 1 % of the

general populationin 8% of still birthsand in close to 50% of spontaneously aborted

fetuses. The 3 10!base pairs that encode the human genome are pac"aged into #3 pairs of

chromosomes$ hich consist of discrete portions of &'A bound to seeral classes of

regulatory proteins. Technical adances that led to the abil ity to analye human

chromosomes immediately translated into the reelation that human disorders can be caused

by an abnormality of chromosome number. *n 1!5! the clinical recogniable disorder

&on syndromeas demonstrated to result from haing three copies of chromosome #1

(trisomy #1). +ery soon thereafter in 1!,0a small structurally abnormal chromosome

as recognied in the cells of some patients ith chronic myelogenous leu"emia (-/)

and this abnormal chromosome is no "non as the hiladelphia chromosome.

ince these early discoeriesthe techni2ues for analysis of human chromosomes

and &'A in general hae gone through seeral reolutions and ith each technical

adancement our understanding of the role of chromosomal abnormalities in human

disease has epanded hile early studies in the 1!50s and 1!,0s easily identified

abnormalities of chromosome number (aneuploidy) and large structural alterations such as

deletions (chromosomes ith missing regions)duplications (etra copies of chromosome

regions) or translocations (here portions of the chromosomes are rearranged)many other

types of structural alterations could only be identified as techni2ues improed. The first

important technical adance as the introduction of chromosome banding in the late 1!,0s

a techni2ue that alloed for the staining of the chromosomes so that each chromosome

could be recognied by its pattern of alternating dar" and light (or fluorescent and

nonfluorescent) bands. 4ther technical innoations ranged from the introduction of

fluorescence in situ hybridiation in the 1!80s to use of arraybased and se2uencing

technologies in the early #000s. -urrently e can appreciate that many types of

chromosome abnormalities contribute to human disease including aneuploidy6 structural

alterations such as deletions and duplications translocations or inersions6 uniparental

disomy here to copies of one chromosome (or a portion of a chromosome) are

inherited from one parent6 comple alterations such as isochromosomes mar"ers and


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rings6 and mosaicism for all of the aforementioned abnormalities. The first chromosome

disorders identified had ery stri"ing and generally seere phenotypes because the

abnormalities inoled large regions of the genome but as methods hae become more

sensitieit is no possible to recognie many more subtle phenotypesoften inoling

smaller genomic region.

METHODS FOR CHROMOSOME ANALYSIS

TA'&A7& -T49:':Tl- A'A/*

tandard cytogenetic analysis refers to the eamination of banded human

chromosomes. ;anded chromosome analysis allos for both the determination of the numberand identity of chromosomes in the cell and recognition of abnormal banding patterns


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associated ith a struA),

are used to specially stimulate groth of T cells in a blood sample. 4ther sources of diiding

cells include s"inderied fibroblasts amniotic fluid or placental tissue (for prenatal

diagnosis),or tumor tissue (for cancer diagnosis). After culturingcells are treated ith a

mitotic spindle inhibitor hich preents the separation of the chromatids during

metaphase. >alting mitosis in metaphase is essential because chromosomes are at their

most condensed state during this stage of mitosis. The banding pattern of a metaphase

chromosome is easily recogniable and is ideal for "aryotyping. There are seeral different

types of chromosome staining techni2ues including 7banding -banding and

2uinacrine stainingbut the most commonly used is 9banding. 9banding is accomplished

by treatment of the chromosomes ith a proteolytic enyme,such as tripsinhich digests

some of the proteins holding &'A in a threedimensional structure

folloed by stainingith a dye (9iemsa) that binds &'A. The resulting patterns hae both dar" and light bands6

in generalthe light bands occur in regions on the chromosome in hich genes are actiely

being transcribedand dar" bands are in regions of less actie transcription.

The banded human "aryotype has no been standardied based on an internationally

agreed upon system for designating not an indiidual chromosomes but also chromosome

regionsproiding a ay in hich structural rearrangements and ariants can be described

in terms of their composition. The normal human female "aryotype is referred to as ?,@@

(?, chromosomes ith ## pairs of autosomes and to of the same type of se

chromosomes to @sBindicating this is a female)6 and the normal human male "aryotype

is referred to as ?,@ (?, chromosomesith ## pairs of autosomes and one of each

type of se chromosome one @ and one ] indicating this is a male). The anatomy of a

chromosome includes the central constriction"non as the centromerehich is critical

for moement of the chromosomes during mitosis and meiosis6 the to chromosome arms (p


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for the smaller or petite armand 2 for the longer arm)6 and the chromosome endshich

contain the telomeres. The telomeres are made up of a heanucleotide repeat (TTA999)n

and unli"e the centromerethey are not isible at the light microscope leel. Telomeres are

functionally important because they confer stability to theend of the chromosome. ;ro"en

chromosome tend to fuse end to end hereas a normal chromosome ith an intact

telomere structure is stable. To create the standard chromosomebanding map each

chromosome is diided into segments that are numberedand then further subdiided. The

precise band names are recorded in an international document so that each band has a distinct

number Cigure 83el shos an ideogram (chromosome map ith bands) of the @

chromosome and a 9banded @ chromosome. This system proides a ay for a chromosome


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abnormality to be rittenith an indication of hich band is deletedduplicatedor

rearranged.


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MOLECULAR CYTOGENETlCS

olecular cytogenetics proides a lin" beteen chromosome and molecular analysis

and oercomes some of the limitations of standard cytogenetics. &eletions smaller than

seeral million base pairs are not routinely detectable by standard 9banding techni2ues

and chromosomal abnormalities ith indistinct or noel banding patterns can be difficult or

impossible to interpret. To carry out cytogenetic analysiscells must be diidinghich is

not alays possible to obtain (e.g. in autopsy or tumor material that has already been fied).

Cinallygroth selection or bias may occasionally cause the results of cytogenetic studies

to be misleading because cells that proliferate in itro may not be representatie of the

original population as is often the case ith tumor specimens. Cluorescence in situ

hybridiation (C*>) is a combined cytogeneticmolecular techni2ue that soles many of the

aforementioned problems. C*> permits determination of the number and location of specific

&'A se2uences in human cells. C*> can be performed on metaphase chromosomes as

ith 9banding$but can also be performed on cells not actiely progressing through mitosis.

C*> performed on nondiiding cells is referred to as interphase or nuclear C*> (Cig. 83e

#). The C*> procedure relies on the complementarity beteen the to strands of the &'A

double heli and uses a molecular probehich can be a pool of se2uences across an entire

chromosome,a &'A se2uence for a repetitie part of the genome (e.g., centromeres or

telomeres)or a specific &'A se2uence found only once in the genome (e.g.,a disease

associated gene). The choice of probes for C*> studies is important and ill ary ith the

information needed for the diagnosis of a particular disorder. The most common type of

probes are locusspecific probes,hich are used to determine if a critical gene or region is

absent (indicating a deletion), or present in the normal number of copies or if an

additional copy of the region is present. C*> on metaphase chromosomes ill gie the

additional information of the location of the additional copy hich is necessary


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information to determine hether a structural rearrangementsuch as a translocation is

present. C*> can also be performed ith probes that bind to repeated se2uencessuch as

&'A found in centromeres or telomeresor ith probes that bind to an entire chromosome

(DpaintingD probes), to determine the chromosome composition of an abnormal

chromosome. *nterphase C*> studies can also help to identify structural alterations hen

probes are used that map to both sides of a translocation brea"point. :ach side of the

brea"point is labeled in a different color and hen no translocation is present the to

probes appear to be oerlapping. hen a translocation is present the to probes appear

separate from one another. These set of probes called Dbrea" apartD probes are

commonly used to detect recurrent translocations in cancer cells.


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ARRAY-BASED METHODOLOGIES (CYTOGENOMICS)

Arraybased methods ere introduced into the clinical lab beginning in #003 and

2uic"ly reolutionied the field of cytogenetics. These techni2ues used arrays (collections of

&'A segments from the entire genome) hich could be interrogated ith respect to copy

number. ith standard cytogenetics the missing or etra pieces of &'A hae to be big

enough to see in the microscope on banded chromosomes (usually larger than 5 b). C*>

re2uires a preselection of an informatie molecular probe prior to analysis. *n contrast

arraybased techni2ues permit analysis of many regions of the genome in a single analysis

ith greatly increased resolution oer standard cytogenetics. Arraybased techni2ues allo

for scanning of the genome for small deletions or duplications 2uic"ly and accurately. The

resolution of the test is a function of the number of probes or &'A se2uences present on the

array. Arrays may use probes of different sies (ranging from 50 to #00000 base pairs of

&'A) and different probe densities depending on the re2uirements of the application. /o

resolution platforms can hae hundreds of probes targeted to "non disease regions

hereas highresolution platforms can hae millions of probes spread across the entire

genome. &epending on the sie of the probes and the probe placement across the

genome $arraybased testing may be able to detect single eon deletions or duplications.


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Comparativ G!omi" H#$ri%i&atio! (CGH) a!% Si!'l N"loti% ol#morp*i+m (SN) A!al#+i+

-9> and 'based genotyping arrays can both be used for the analysis of genomic

deletions and duplications. Cor both techni2uesoligonucleotide probes are placed onto a

slide or chip in a grid format. :ach of these probes is specific for a particular genomic region.

*n array -9>the amount of &'A from a patient is compared to that in a clinically normal

control or pool of controls for each of the probes present on the array. &'A from a

patient is fluorescently labeled ith a dye of one colorand &'A from a control indiidual

is labeled ith another color. These &'A samples are then hybridied at the same time to the

array. The resulting fluorescent signal ill ary depending on hether both the control and

patient &'A are present in e2ual amounts or if one has a different copy number than the

other. ' platforms use arrays targeting 's that are distributed across the genome. '

arrays arE in density of mar"ers and in the technology used for g enotypingdepending on

the manufacturer of the array. ' arrays ere initially designed to determine genotypes at a

biallelicpolymorphic base (e.g.---Tor TT) and hae been increasingly used in

genomeide association studies to identify disease susceptibility genes. ' arrays ere

subse2uently adapted to identify genomic deletions and duplications (Cig. 83e#) '

arrays in addition to identifying copy number changes can also detect regions of the

genome that hae an ecess of homoygous genotypes and absence of heteroygous

genotypes (e.g. -- and TT genotypes only ith no -T genotypes). Absence of

heteroygosity is sometimes associated ith uniparental disomy (discussed later in this

chapter) but is also obsered hen an indiidualFs parents are related to one another (identity

by descent). 7egions of homoygosity hae been used to help identify genes in hich

homoygous mutations result in disease phenotypes in families ith "non consanguinity.

Arraybased techni2ues (hich e ill no refer to as cytogenomic analysis) hae

proen superior to chromosome analysis in the identification of clinically significant

deletions or duplications. *t is estimated that for a deletion or duplication to be isualied by

standard cytogenetics it must be minimally beteen 5 and 10 million base pairs in sie. *n

almost all casesdeletions and duplications of this sie contain multiple genesand these

deletions and duplications are disease causing. >oeer utiliation of arraybased


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cytogenomic testinghich can routinely identfydeletions and duplications, smaller

than 50.000 base pairs reeals that clinically normal indiiduals all hae some deletions

and duplications. This presents a dilemma for the analyst to discern hich smaller copy

number ariations (-'+s) are disease causing (pathogenic) and hich are li"ely benignpolymorphisms. Although initially burdensome the cytogenomics community has been

curating these -'+ s for almost a decadeand databases hae been created reporting -'+s

routinely seen in clinically normal indiiduals and those routinely seen in indiiduals ith

clinical abnormalities. 'eertheless each copy number ariant that is identified in an

indiidual undergoing genomic testing must be ealuated for gene content and oerlap ith

-'+s in other patients and in controls. Array technologies are &'A based unli"e

cytogenetic technologieshich are cell based. Although resolution of gains and losses are

greatly increased ith array technology this techni2ue cannot identified structural

changes. hen &'A is etracted for array studieschromosomal structure is lost because

the &'A is fragmented for better hybridization to theslides. As an eamplethe array

may be able to detect a duplication of a small region of a chromosome but no information

on the location of this etra material can be determined from this test. The location of this

etra copy in the genome may be critical

as the chromosomal material may be inoled in

a translocation insertionmar"eror other comple rearrangement. &epending on the

chromosomal position of this etra material the patient may hae different clinical

outcomes and recurrence ris"s for the family can be significantly different. 4ften

combinations of arraybased and cytogeneticbased techni2ues are re2uired to fully

characterie chromosomal abnormalities (see Table 83el for comparison ofthese

technologies).

NE,T - GENERATIONSEUENCING-BASED METHODOLOGIES

7ecent adances in genomic se2uencing "non as netgeneration se2uencing

('9)$ hae astly increased the speed and through put of &'A se2uence analysis. '9 is

rapidly finding its ay into the diagnostic lab for detection of clinically releant intragenic

mutations$ and ne bioinformatic tools for analysis of genomic deletions and duplications are

being deeloped. *t is anticipated that '9 ill soon allo the complete analysis of a


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patientFs genome ith identification of intragenic mutations as ell as chromosome

abnormalities resulting in gain or loss of genetic material. *dentification of completely

balanced translocations is the most challenging for '9but recent reports of sucsesses in

this area suggest that in a matter of time$ se2uencing ill be used for all types of genomic

analysis.

INDICATIONS FOR CHROMOSOME.CYTOGENOMIC ANALYSIS

-ytogenetic analysis is most commonly used for (1) eamination of the fetal

chromosomes or genome during pregnancy (prenatal diagnosis) or in the eent of a

spontaneous miscarriage6 (#) eamination of chromosomes in the neonatal or pediatric

population to loo" for an underlying diagnosis in the case of congenital or deelopmental

anomalies including short stature and abnormalities of seual differentiation or

progression6 (3) chromosome analysis in adults ho are facing fertility problems6 or (?)

eamination of cancer cells to loo" for alterations that aid in establishing a diagnosis or

contributing to the prognosis of a tumor (Table 83e#).

RENATAL DIAGNOSIS

renatal diagnosis is carried out by analysis of samples obtained by four techni2uesG

amniocentesischorionic illous sampling fetal blood sampling and analysis of cell

free &'A from maternal serum. Amniocentesishich has been the most commonly used

test to dateis usually performed beteen 15 and 1H ee"s of gestational age and carries a

small but significant ris" for miscarriage. Amniocentesis can be performed as early as 1#


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ee"s but because there is a loer olume of fluid the ris"s for fetal in=ury or

miscarriage are greater. -horionic illous sampling (-+) or placental biopsy is routinely

carried out earlier than amniocentesisbeteen 10 and 1# ee"sbut a reported increase

in limb defects hen the procedure is carried out earlier than 10 ee"s has resulted in

reduced use of this test in some centers. Cetal blood sampling (percutaneous umbilical blood

sampling I;B) is a ris"ier procedure that is carried out in the second or third trimester of

pregnancy usually to follo up on an unclear finding from an amnio centesis (such as

mosaicism) or an ultrasound abnormality that as detected later in pregnancy. 4ne of the far

reaching recent adances in prenatal diagnosis of chromosome and other genetic disorders is

the utiliation of cell free fetal &'A that can be identified in maternal serum. The obious

adantages of using fetal &'A obtained from maternal serum is that the &'A can be

obtained at minimal ris" to the pregnancy, because it re2uires a maternal blood sample

rather than amniotic f1uid hich is obtained by puncturing the uterine membranes and carries

a ris" of miscarriage or infection. Although cell free fetal &'A screening also called

noninasie prenatal screening has started to be offered clinically. it re2uires further

confirmation of fetal tissues hen an abnormal result is identified. Curthermore ethical

concerns hae been raised because it is feared that the ease of doing this test may

encourage testing for indiiduals ho are not truly prepared to deal ith the choices that

accompany diagnosis of a genetic disease and this testing may change the ethical implications

of prenatal testing. 'eerthelessthis is an actie of area of researchboth in terms of the

technology and the utiliation and implications.


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Commo! I!%i"atio!+

-ommon indications for prenatal diagnosis by cytogenetic or cytogenomic analysis are (1)

adanced maternalnal, (#) presence of an abnormality of the fetus on ultrasound

eamination, and (3) abnormalities in maternal serum screening that reeal an increased ris"

for chromosome abnormality. aternal age is ell "non to be an important ris" factor for

haing a fetus ith trisomy. At a maternal age less than #5 years #% of all clinically

recognied pregnancies are trisomic but by a maternal age of 3, years this figure

increases to 10% and by the maternal age of ?# years the figure increases to J33%.

;ased on the ris" of haing a chromosomally abnormal fetus in comparison to the ris" for an

aderse eent from amniocentesis or -+the recommendation is that omen oer the age

of 35 consider prenatal testing if they ant to "no the chromosomal status of their fetus.

The precise mechanism for the maternal age effect is not "nonbut it is belieed that it

inoles a brea"don in the process of chromosome segregation. A similar effect is not seen

for trisomy and paternal age. This difference may ref1ect the fact that oocytes are generated

early in oary deelopment in the female here as spermatogonia are generated

continuously after puberty in the male. Abnormalities on prenatal ultrasound are the second

most fre2uent indication for prenatal genetic screening. Iltrasound screening can reeal

structural or functional anomalies in the fetushich might be associated ith chromosome

or genomic disorders. Colloup chromosome studies may therefore be recommended.

aternal serum screening results are the third most fre2uent indica tion for prenatal

chromosome analysis. There hae been seeral ersions of maternal serum screening offered

oer the past fe decades -urrently the D2uadD screen analyes leels of Kfetoprotein

(AC)human chorionic gonadotropin (h-9)estriol, and inhibinA. The alues of these

analytes are used to ad=ust the maternal agepredicted ris" of a trisomy #1 or trisomy 18 fetus.

OSTNATAL INDICATIONS

ostnatal indications for cytogenetic or cytogenomic analysis in neonates or children

are ariedand the list has been groing ith the increasing ability to diagnose smaller

genomic alterations ia arraybased techni2ues. -ommon indications include multiple con

genital anomalies suspicion of a "non cytogenetic or cytogenomic syndrome

intellectual disability or deelopmental delay both ith and ithout accompanying

dysmorphic features autism failure to thrie in infancy or short stature during


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childhood and disorders of seual deelopment. The ability to detect smaller genomic

alterations ith inolement of feer genessometimes as fe as a single genesuggests

that a ider range of phenotypes could be inestigated by cytogenomic analysis. 7easons for

chromosome testing in adults include recurrent miscarriages or infertilityhere balanced

chromosome rearrangements such as reciprocal translocations may occur. Additionally

some adults ith anomalies ho ere not diagnosed hen they ere children are referred for

cytogenetic analysis often hen other members of their family ant to understand any

potential genetic implicationsas they plan their on families.

TYES OF CHROMOSOME ABNORMALlTIES

NUMERICAL CHROMOSOME ABNORMALlTIES

A!ploi%# (etra or missing chromosomes) is the most common type of

abnormality$ occurring in 3L1000 neborns and at much higher fre2uency (about 35%) in

spontaneously aborted fetuses. The only autosomal trisomies that are compatible ith being

lie born in humans are trisomies 13 18 and #1 although there are seeral

chromosomes that can be trisomic in mosaic form. Trisomy #1 is associated ith the

relatiely common disorder &on syndrome. &on yndrome has characteristic features

including recogniable facial features$ along ith intellectual disability and abnormalities of

multiple other organ systems including the heart. ;oth trisomy 13 and trisomy 18 are much

more seere disorders than &on syndromeith lo fre2uency of patients suriing past

1 year of age. Trisomy 13 is characteried by lo birth eight postaial polydactyly

microcephaly ocular malformations such as anophthalmia or microphthalmia cleft lip

and palate cardiac defects$ and renal malformations. Trisomy 18 neonates hae distinct

facial characteristics at birth accompanied by an abnormal neurologic eam

underdeeloped genitaliageneral lac" of responsienessand structural birth defects such


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as congenital heart diseaseesophageal atresiaand omphalocele. osaicism refers to the

presence of to or more populations of cells ith distinct chromosome constitutionsG for

eample$ an indiidual ith a normal female "aryotype in some cells (?, @@) and trisomy

#1 in other cells (?H @@ M#1). *n general indiiduals ho are mosaic for a

chromosomal abnormality hae less seere phenotypes than indiiduals ith that same

finding in eery ce11. The seerity and presentation of phenotypes are related to the mosaic

leels and the tissue distribution of the abnormal cells. There are a number of trisomies that

hae been reported in mosaic form including mosaic trisomies for chromosomes 8 !

1?1Hand ##. A number of trisomies hae also been reported in spontaneous abortions

(A;s) that hae not been seen in lieborn indiiduals including trisomy 1,hich is the

most common trisomy in A;s. onosomy for human chromosomes is ery rareith the

single eception being monosomy for the @ chromosome$ associated ith Turner syndrome

(?5@). onosomy for the @ chromosome occurs in 1 % of all conceptionsyet !8% of

these conceptions do not go to term and result in A;s. Trisomies for the se chromosomes

also occurith ?H@@@ (trisomy @ or triple @ yndrrome), ?H@@ (Nlinefelter

syndrome) and ?H @ all reported in indiiduals ith relatiely mild phenotypes

(-hap. ?10). Nlinefelter syndrome is the most common clinically recognied se

chromosome abnormality and clinical features include gynecomastia aoospermia

small testesand hypogonadism. The ?H@ "aryotype is most often found in boys ith

deelopmental delay and or behaioral difficulties but populationbased studies hae

shon that intelligence for indiiduals ith this "aryotype is generally ithin the normal

rangealthough slightly loer than that found in siblings.

STRUCTURAL CHROMOSOME ABNORMALlTIES

tructural chromosome abnormalities include deletions duplications$

translocationsinersionsas ell as other types of abnormalitieseach relatiely rare$

but nonetl1eless contributing to clinical disease resulting from chromosome anomalies. These

rare alterations include isochromosomes ring chromosomesdicentric chromosomes

and mar"er chromosomes (structurally abnormal chromosomes that cannot be identified

based on cytogenetics alone). ;oth translocations and inersions can be completely balanced

in some casessuch that there is no disruption of coding regions of the genomeith a


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completely normal clinical phenotype6 hoeercarriers are at ris" for unbalanced forms of

these rearrangements in their offspring

7eciprocal translocation 5 are found in approimately 1L5001L,00 indiiduals in the

general population and result from the echange of chromosomal segments beteen at least

to chromosomes. These usually occur beteen nonhomologous chromosomes and can be

identified based on an altered banding pattern on 9banding. ;alanced translocation carriers

are at ris" for abnormal chromosome segregation during meiosis and therefore hae a higher

ris" for infertilityA;and lieborn offspring ith multiplecongenital malformations.

These phenotypes are obsered hen only one of the pairs of chromosomes inoled in a

translocation is inherited from a parentresulting in an unbalanced genotype (Cig. 83e3).

ometimes the echanged segments are so small that they cannot be appreciated by banding

(cryptic translocation), and these are sometimes recognied hen a phenotypically affected

child ith an unbalanced form is born. arental chromosomes can then be studied by C*> to

determine if the rearrangement is inherited from a parent ith a balanced form of the

translocation. The ma=ority of reciprocal apparently balanced translocations occur in

phenotypically normal indiiduals. The ris" for a clinical abnormality hen a ne reciprocal

translocation is identified (usually during prenatal diagnostic studies) is about H%. Analysis

of cytogenetically reciprocal translocations using arrays has demonstrated that translocations

in clinically normal indiiduals are more li"ely to sho no deletions or duplications at the

brea"pointhereas translocations in clinically affected indiiduals are more li"ely to hae

brea"pointassociated deletions or duplications. ost recip rocal translocations occur

uni2uelyat apparently random positions throughout the genome6 hoeer there are a

fe eceptions ith multiple cases of recurrent translocations occurring. These recurrent

translocations include t(1l6##) hich results in :manuel syndrome in the unbalanced

formand seeral translocations inoling a region on ?p8pand 1#p. These recurrent

translocations occur in regions of the genome that contain specific types of AT rich repeats

or other repeat se2uences that are prone to rearrangement. A special category of

translocations is the 7obertsonian translocations hich inole the acrocentric

chromosomes. An acrocentric chromosome has uni2ue genetic material only on the long arm

of the chromosomes hereas the short arm contains repetitie &'A. The acrocentric

chromosomes are 131?15#1and ##. 7obertsonian translocations occur hen an


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entire long arm of an acrocentric chromosome is translocated onto the short arm of another

acrocentric chromosome. ;alanced carriers of a 7obertsonian translocation contain only ?5

chromosomes ith one chromosome consisting of to long arms of an acrocentric

chromosome. Technically

this is an unbalanced translocation

as to short arms of the

acrocentric chromosomes are missing6 hoeer because the short arms are repetitie

there is no phenotypic conse2uence Inbalanced 7obertsonian carriers hae ?,

chromosomesbut hae three copies of the long arm of an acrocentric chromosome. The

most common 7obertsonian translocation inoles chromosomes 13 and 1?. Inbalanced

7obertsonian translocations inoling chromosomes 13 and #1 result in trisomy 13 and

&on syndrome, respectiely Approimately ?% of patients ith &on syndrome hae a

translocationand because recurrence ris"s are different for families of these indiiduals

all patients ith clinically identified &on syndrome should hae a "aryotype to loo" for

translocations.

*nersions are another type of chromosome abnormality inoling rearranged

segments, here there are to brea"s ithin a chromosome ith the interening

chromosomal material inserted in an inerted orientation. As ith reciprocal translocations,

if a brea" occurs ithin a gene or control region for a gene a clinical phenotype may

result, but often there are no conse2uences for the inersion carrier 6 hoeerthere is ris"

for abnormalities in the offspring of carriersas recombinant chromosomes may result after

crossing oer beteen a normal chromosome and an inerted chromosome during meiosis.

&eletion refers to the loss of a chromosomal segmenthich results in the presence of only

a single copy of that region in an indiidualFs genome. A deletion can be at the end of a

chromosome (terminal)or it can be ithin the chromosome (interstitial). &eletions that are

isible at the microscopic leel in standard cytogenetic analysis are generally greater than 5

b in sie. maller deletions hae been identified by C*> and by chromosomal microarray.

The clinical conse2uences of a deletion depend on the number and function of genes in the

deleted region. 9enes that cause a phenotype hen a single copy is deleted are "non as

haploinsufficient genes (one copy is not sufficient), and it is estimated that less than 10% of

genes are haploinsufficient. 9enes associated ith disease that are not haploinsufficient

include genes for "non recessie disorderssuch as cystic fibrosis or Tayachs disease.

The first chromosome deletion syndromes ere diagnosed clinically and ere subse2uently

demonstrated to becaused by a chromosome deletion on cytogenetic analysis. :amples of


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these disorders include the olf>irschhorn syndromehich is associated ith deletions

of a small region of the short arm of chromosome ? (?p) the criduchat

syndromeassociated ith deletion of a small region of the short arm of chromosome 5

(5p)6 illiams syndromehich is associated ith interstitial deletions of the long arm of

chromosome H (H2l1.#3)6 and the &i9eorgeLelocardiofacial syndromes associated ith

interstitial deletions of the long arm of chromosome ## (##2 11.#). *nitial cytogenetic studies

ere able to proide a rough localiation of the deletions in different patientsbut ith the

increased usage of arraysprecise mapping of the etent and gene content of these deletions

has become much easier. *n many casesone or to genes that are critical for the phenotype

associated ith these deletions hae been identi fied. *n other cases the phenotype stems

from the deletion of multiple genes. The increased utiliation of genomic testing by array

hich can identified deletions that are much smaller than those detectable by standard

cytogenetic analysishas resulted in the discoery of seeral ne cytogenomic disorders.

These include the l2#1.115213.31,p11.#and 1H 2#1.31 microdeletion syndromes.

&uplication of genomic regions is better tolerated than deletion as eidenced by the

iability of seeral autosomal trisomies (hole chromosome duplications) but no autosomal

monosomies (hole chromosome deletions). There are seeral duplication syndromes here

the duplicated region of the genome is present as a supernumerary chromosome. Itiliation

of chromosome microarray analysis has made analysis of the origins of duplicated

chromosome material straightforard (Cig. 83O#). 7ecurrent syndromes associated ith

supernumerary chromosomes include the inerted duplication 15 (in dup 15) syndrome

caused by the presence of a mar"er chromosome deried from chromosome 15ith to

copies of proimal 152 resulting in tetrasomy (four copies) of this region. The indup 15

syndrome has a distinct phenotype and is associated ith hypotonia deelop mental

delay intellectual disabilityepilepsyand autistic behaior. Another syndrome is the

cat eye syndromenamed for the Dcateyeli"eD appearance of the pupilresulting from a

coloboma of the iris. This syndrome results from a supernumerary chromosome deried from

a portion of chromosome ##and the mar"er chromosomes can ary in sie and are 4ften

mosaic. -onsistent ith epectations of a mosaic disorderthe phenotype of this syndrome

is highly ariable and includes renal malformationsurinary tract anomaliescongenital

heart defects anal atresia ith fistula imperforate anus and mild to moderate


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intellectual disability. Another rare duplication syndrome is the allisterNillian syndrome

(N) hich illustrates the principle of tissuespecific mosaicism. *ndiiduals ith N

hae coarse facial features ith pigmentary s"in anomalieslocalied alopeciapro found

intellectual disability and seiures. The disorder is caused by a supernumerary

isochromosome for the short arm of chromosome 1# (isochromosome 1#p). *sochromosomes

consist of to copies of one chromosome arm (p or 2)rather than one copy of each arm.

This isochromosome is not generally seen in peripheral blood *ymphocytes hen they are

analyed by 9banding but it is detected in fibroblasts. Array technology has been

reported to detect the isochromosome in uncultured peripheral blood in some patients and

it has been hypothe sied that a groth bias against cells ith the isochromosome preents

their identification in cytogenetic studies.

'umerical abnormalities translocations and deletions are the most common

chromosome alterations obsered in the diagnostic laboratorybut in addition to inersions

and duplications seeral other types of abnormal chromosomes hae been reported

including ring chromosomes here the to ends of the chromosome fuse to form a

circle and insertions here a piece of one chromosome is inserted into another

chromosome or elsehere into the same chromosome.

Uniparental disomy (UPD)is the inheritance of a pair of chromosomes (or part of a

chromosome) from only one parent. This usually occurs as a result of nondis=unction during

meiosis ith a gamete missing or haing an etra copy of a chromosome. A result ing

fertilied egg ould then hae only one parental contribution for a gien chromosomepair

or a trisomy for a gien chromosome. *f the monosomy or trisomy is not compatible ith

life

the embryo may undergo a DrescueD to normal copy number. *f a monosomy is

rescuedthe single chromosome may be duplicatedresulting in a cell ith to identical

chromosomes (monosomy rescue) (Cig. 83e?). *n the case of trisomies a subse2uent

nondis=unction can result in cells here one of the etra chromosomes is lost (trisomy rescue)

(Cig. 83e?). Cor trisomy rescuethere is a one in three chance that the lost.


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