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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