Cytogenetics/

Chromosomal
Genetics
SBM 2083
Norafiza Zainuddin

Cytogenetics Terms and

Definitions
Cytogenetics = the study of chromosomes and
their abnormalities
Karyotype = a display of chromosomes ordered
according to length (size) and physical landmarks
that appear during mitotic metaphase, when DNA
coils tightly
Karyotyping = a karyotype analysis to examine
chromosomes in a sample of cells, which can help
identify genetic abnormalities as the cause of a
disorder or disease
Karyotyping can
count the number of chromosomes
look for structural changes in chromosomes

Idiograms = schematic /stylized diagram

Introduction to
Cytogenetics

Introduction to
Cytogenetics
In order to study chromosomes, cells
must be capable to grow and divide
rapidly in culture.
Most suitable cells WBC (Tlymphocytes)
Includes routine analysis of G-Banded
chromosomes, other cytogenetic
banding techniques, as well as
molecular cytogenetics such as
fluorescent in situ hybridization (FISH)
and comparative genomic hybridization
(CGH)

A metaphase cell positive for

the bcr/abl rearrangement
using FISH.

Why do we need to analyze

chromosomes?

Clinical Indications for

Chromosome Analysis
Chromosome analysis = a routine diagnostic
procedure for a number of specific phenotypes
encountered in clinical medicine
Exception when there is non-specific general
clinical situations and findings that indicate a
need for cytogenetic analysis

Clinical Indications for Chromosome

Analysis
Clinical
Indications

Details

Problems of
early growth
and
development.

Failure to thrive, developmental delay, dysmorphic facies,

multiple malformations, short stature, ambiguous genitalia,
and mental retardation are frequent findings in children
with chromosome abnormalities, although they are not
restricted to that group. Unless there is a definite nonchromosomal diagnosis, chromosome analysis should be
performed for patients presenting with a combination of
such problems.

Stillbirth and
neonatal
death.

Chromosome analysis should be performed for all stillbirths

and neonatal deaths that might have a cytogenetic basis to
identify a possible specific cause or, alternatively, to rule
out a chromosome abnormality as the reason for the loss. In
such cases, karyotyping should be performed to provide
accurate genetic counseling and information for prenatal
diagnosis in future pregnancies.

Fertility
problems.

Chromosome studies are indicated for women presenting

with amenorrhea and for couples with a history of infertility
or recurrent miscarriage. A chromosome abnormality is
seen in one or the other parent in a significant proportion

Clinical Indications for Chromosome

Analysis
Clinical
Indications

Details

Family history.

A known or suspected chromosome abnormality in a firstdegree relative is an indication for chromosome analysis
under some circumstances.

Neoplasia.

Almost all cancers are associated with one or more

chromosome abnormalities. Chromosome and genome
evaluation in the appropriate tissue sample (the tumor
itself, or bone marrow in the case of hematological
malignant neoplasms) can provide useful diagnostic or
prognostic information.

Pregnancy in a
woman of
advanced age.

There is an increased risk of chromosome abnormality in

fetuses conceived by women older than 35 years. Fetal
chromosome analysis should be offered as a routine part of
prenatal care in such pregnancies.

How Do We Analyze
Chromosomes?
Collecting a
living tissue
(usually
blood)

Staining
with a
designated
nuclear stain

Photographing the
metaphase
spreads of
chromosomes on
the slide

Culturing the tissue for

the appropriate amount
of time (48-72 hours for
peripheral lymphocytes)

Rupturing the
cell nucleus with
a hypotonic
saline solution

Placing the
cell sediment
on a slide

Arranging the 22 pairs of

autosomes according to length;
sex chromosome on right-hand
corner

Adding
colcemid to
produce
metaphase
arrest

Harvesting
the cells

Karyotype

The Human Karyotype

Chromosomes can be
differentiated by length
and location of the
centromere
The centromere is apparent
as a primary constriction of
the sister chromatids due to
formation of the kinetochore
This is a recognizable
cytogenetic landmark,
dividing the chromosome
into two arms, a short arm
designated p (for petit) and
a long arm designated q

Metaphase
chromosomes can be
analyzed directly under
the microscope, but
usually experts will cut
out the chromosomes
from a photomicrograph
and arrange them in
pairs in a standard
classification
The completed picture
is called a karyotype

The Human Karyotype

Karyotype refers to
the number and type of
chromosomes present
in an individual
Karyogram is now
often used to designate
the printed display of
chromosomes
Currently, computerized
image analyzers are
usually used to display
chromosomes
After sorting by size,
chromosomes are
further classified
according to the
position of the

A karyogram of a normal male. The

banded metaphase chromosomes are
arranged from largest to smallest.

How do scientists read

chromosomes?
To "read" a set of human
chromosomes, scientists first use
three key features to identify their
similarities and differences:
1.Size
The easiest way to tell two different
chromosomes apart

2.Banding pattern
The size and location of Giemsa
bands on chromosomes make each
chromosome pair unique

3.Centromere position
. Using these key features, scientists
match up the 23 pairs one set
from the mother and one set from
the father.

The Human Karyotype

A normal female karyotype is designated
46,XX
A normal male karyotype is designated 46,XY
(The nomenclature for various chromosome
will be discussed under ISCN)

Chromosome Banding
Early karyotypes were useful in counting the
number of chromosomes, but unable to
detect structural abnormalities (eg. balanced
rearrangements or small chromosomal
deletions)
Staining techniques were then developed
chromosome banding
Helps detect deletions, duplications, and other
structural abnormalities
Facilitates the correct identification of individual
chromosomes

Chromosome Banding
The 24 types of
chromosome found in
the human genome can
be readily identified at
the cytological level by
a number of specific
staining procedures

4. Special cytological procedures

i.

centromeric region and regions

containing constitutive
heterochromatin (sections of
chromosomes 1q, 9q, and 16q)
adjacent to the centromere and the
distal part of Yq. Heterochromatin is
the type of chromatin defined by its
property of remaining in the
condensed state and staining darkly
in interphase cells.

Staining methods:
1.

G banding: Giemsa

2.

Q banding:
Quinacrine

3.

R banding: Reverse

C banding - Involves staining the

ii.

High resolution banding

prometaphase banding

iii. Fragile sites non-staining gaps

Chromosome Banding
G banding
Definition = a technique used in cytogenetics to produce
a visible karyotype by staining condensed chromosomes
Most commonly used method
Technique:
Metaphase chromosomes are treated with trypsin (to partially digest
the chromosome) and stained with Giemsa

Banding pattern: Alternating light and dark bands (G

bands)
Associated with features of DNA sequence, such as base
composition (i.e., the percentage of base pairs that are GC or AT)
and the distribution of repetitive DNA elements.
Dark bands take up the stain strongly A,T rich (gene poor)

Application:
All chromosomes can be individually distinguished
Any structural or numerical abnormalities eg. translocation can be

G banding (cont.)

Ideogram showing G-banding patterns for human chromosomes at

metaphase, with about 400 bands per haploid karyotype.
As drawn, chromosomes are typically represented with the sister chromatids so
closely aligned that they are not recognized as distinct structures. Centromeres are
indicated by the narrow dark gray regions separating the p and q arms. For
convenience and clarity, only the G-positive bands are numbered.

G banding (cont.)

Examples of G-banding patterns for chromosomes 5, 6, 7, and 8 at

the 550-band stage of condensation.
Band numbers permit unambiguous identification of each G-dark or G-light
band, for example, chromosome 5p15.2 or chromosome 8q24.1. (Redrawn

Chromosome Identification
Q Banding
Definition = A fluorescent stain for chromosomes, useful in
identifying the Y chromosome and certain DNA
polymorphisms and heteromorphisms.
Technique:
Staining with quinacrine mustard or related compounds
Then, examine under fluorescence microscopy

Banding pattern:
Specific pattern of bright and dim bands (Q bands)
Banding patterns are similar to those obtained with G-banding stain
Centromeric regions of human chromosomes 3, 4, and 13 are
specifically stained, as are satellites of some acrocentric chromosomes
and the end of Yq chromosome;

Application:
To detect occasional variants in chromosome morphology or staining,
called heteromorphisms
These variants are generally benign and reflect differences in the amount or
type of satellite DNA sequences at a particular location along a chromosome.

The most distinctive heteromorphism brightly fluorescent distal Yq

Chromosome Identification
R banding
Definition = a reverse Giemsa chromosome banding
method that produces bands complementary to G-bands
Technique:
Induce by treatment with high temperature, low pH, or acridine orange
staining
Then, stain with Giemsa
Often used together with G-banding on human karyotype to determine
whether there are deletions

Banding pattern:
The resulting dark and light bands are the reverse of those produced by
G or Q banding (R bands)

Application:
Used specially when regions are poorly-stained by G or Q banding
Standard method in laboratories in Europe

Fluorescence in situ hybridization

(FISH)
Definition = a technique in which a labeled probe
is hybridized to metaphase, prophase, or
interphase chromosomes
Application = to test for missing or additional
chromosomal material as well as chromosome
rearrangements

Fluorescence in situ hybridization (FISH)

A, A fluorescence in situ hybridization (FISH) result. The thinner

arrows point to a centromere-hybridizing probe for chromosome 17,
and the thicker arrow points to a probe that hybridizes to 17p. The
latter probe reveals only one spot in this individual, who has a
deletion of 17p, producing the Smith-Magenis syndrome. (Courtesy of Dr.
Arthur Brothman, University of Utah Health Sciences Center.) B, Face of an infant girl with

Fluorescence in situ hybridization

(FISH)
Representative
results of
chromosome 17 CGH
analysis confirmed
by FISH of the p53
locus in three cases
of malignant
pheochromocytoma
(PCC)
(a) Malignant PCC not
showing loss or
gain in CGH and
FISH analysis
(b)Malignant PCC
with loss of 17p in
the CGH analysis,
including the p53
gene locus, also
showing loss in
FISH

Fluorescence in situ hybridization

(FISH)
Can be extended with multiple colors to detect
several possible alterations of chromosome
number simultaneously
Spectral karyotyping = using multiple probes to
paint each chromosome with a unique color
helps detect structural rearrangements

Fluorescence in situ hybridization

(FISH)

Spectral karyotype. The power of spectral karyotyping is

demonstrated by the identification of a rearrangement between
chromosomes 2 and 22. Note that a portion of chromosome 2
(purple) has exchanged places with a portion of chromosome 22
(yellow). (Courtesy of Dr. Art Brothman, University of Utah Health Sciences Center.)

Comparative Genomic
Hybridyzation (CGH)
The CGH technique, in which differentially labeled
DNA from test and control sources is hybridized to
normal metaphase chromosomes or probes in
microarrays, allows the detection of chromosome
duplications and deletions but not balanced
rearrangements
Array CGH can detect deletions and duplications
shorter than 100 kb and requires only small
amounts of DNA

Chromosome Morphology

Chromosome Morphology and

Nomenclature
Terms

Definition

Centromer The chromosomal locus that regulates the movements of

e
the chromosomes during mitosis and meiosis.
The centromere of mitotic chromosomes can be visualized
as a constricted region where sister chromatids are held
together most closely.
Chromatin

DNA plus the proteins that package it within the cell

nucleus.

Chromoso
me

A DNA molecule with its proteins that moves as an

independent unit during mitosis and meiosis.
Before DNA replication, each chromosome consists of
single DNA molecule plus proteins and is called a
chromatid.
After replication, each chromosome consists of two
identical DNA molecules plus proteins. These are called
sister chromatids.

Kinetocho
re

The centromeric substructure that binds microtubules and

directs the movements of chromosomes in mitosis.

Telomere

The specialized structure at either end of the chromosomal

DNA molecule that ensures the complete replication of the

Chromosome Morphology
Each chromosome contains
one DNA molecule that
stretches between the
telomeres at either end
Naturally occurring
eukaryotic nuclear
chromosomes are
generally linear DNA
molecules with two
telomeres
ELECTRON MICROGRAPH OF A CHROMOSOME FROM WHICH MOST
PROTEINS WERE EXTRACTED, ALLOWING DNA (THIN LINES) TO
SPREAD OUT FROM THE RESIDUAL SCAFFOLD. Enormous amounts of
DNA are packaged in each chromosome. This image shows less than 30% of
the DNA of this chromosome.

Chromosome Morphology

Left, The principal

structural features of
chromosomes.

Center, An electron
micrograph of human
mitotic chromosomes.

Right, A diagram
of the various
classes of
chromosomes.
(Micrograph courtesy of William
C. Earnshaw.)

Chromosome Morphology

Chromosome Morphology

In metacentric chromosomes, the centromere is located midway

along the chromatid
Submetacentric chromosomes have centromeres somewhere
between the middle and the tip (end)
An acrocentric chromosome has its centromere near the tip
Chromosomes 13, 14, 15, 21, and 22
Have small, distinctive masses of chromatin known as satellites attached to their
short arms by narrow stalks (secondary constrictions)
The stalks of these five chromosome pairs contain hundreds of copies of genes
encoding rRNA and a variety of repetitive sequences.

Chromosome Morphology

In telocentric chromosomes, the centromere appears to be

located very near the end of the chromatid
Does not occur in the normal human karyotype, but it is occasionally observed in
chromosome rearrangements

The tip of each chromosome is the telomere

How do scientists find their way

around a chromosome?

With idiograms, researchers can pinpoint the

locations of genes and locate abnormal gene
forms.

International System for Cytogenetic

Nomenclature (ISCN)
ISCN = a consistent numbering system for
mapping genes on chromosomes
Application: To produce relevant idiograms
Idiograms provide a pictorial reference point that
is useful for
locating the positions of individual genes on
chromosomes
identifying various abnormalities associated with a range
of chromosomal disorders

International System for Cytogenetic

Nomenclature (ISCN)
ISCN Rules of Numbering
System:
Numbering system begins
at its centromere
Chromosomes are
assigned a long arm (q)
and a short arm (p), based
on the position of their
centromeres.
The p arm of the
chromosome is always
shown at the top in a
karyotype

Short
arm, p

Long
arm, q

International System for Cytogenetic

Nomenclature (ISCN)
Telomere

Centromer
e

Rules (cont.):
Each arm of the chromosome is then
divided into regions and given
numbers
The numbers assigned to each region
get larger as the distance from the
centromere to the telomere increases
Regions are identified by the presence of
prominent G-bands
The smaller numbers are closest to
centromere (proximal) and the larger
numbers are at the tips (distal; closer to
telomere).

The regions are named p1, p2, etc.,

on the short arm and q1, q2, etc., on
the long arm.

Telomere

International System for Cytogenetic

Nomenclature
(ISCN)
Figure: idiogram for chromosome 12, a
medium-sized chromosome with one
long and one short arm
The position of the centromere, which
separates the p and q arms, is shown
by the hatched area
This particular idiogram depicts the
pattern of Giemsa staining at low
resolution (produces ~400 total bands
in a karyotype; just above the
threshold that is clinically useful)
At this resolution, the long q arm of
chromosome 12 can be subdivided into
two main regions, which are
designated 12q1 and 12q2.

International System for Cytogenetic

Nomenclature (ISCN)
Region 12q1 can be further
subdivided into five subregions,
designated 12q11 through 12q15,
each of which corresponds to a band
detected by Giemsa staining
The more distal 12q2 region can be
subdivided into subregions 12q21
through 12q24
Subregion 12q24 can be further
subdivided into regions 12q24.1
through 12q24.3, even at this
relatively low resolution

International System for Cytogenetic

Nomenclature (ISCN)
Higher resolution: obtained if
staining is done while the
chromosomes are in prometaphase
and are less condensed
~850 bands can be distinguished
Additional subdivisions can be
detected in all of the regions on
chromosome 12 under these
conditions

ISCN Symbols

ISCN Symbols

Abbreviated Terms

add

additional material of unknown origin

arrow ()

from - to, in detailed system

brackets, square
([])

surround the number of cells

cen

centromere

colon, single (:)

break, in detailed system

colon, double (::)

break and reunion, in detailed system

comma (,)

separates chromosome numbers, sex chromosomes, and

chromosome abnormalities

decimal point (.)

denotes sub-bands

del

deletion

de novo

designates a chromosome abnormality which has not been

inherited

der

derivative chromosome

dic

dicentric

dup

duplication

fra

fragile site

heterochromatin, constitutive

hsr

homogeneously staining region

(a tightly packed form of DNA, repetitive, forms

centromeres and telomeres)

ISCN Symbols

Abbreviated Terms

Isochromosome

ins

insertion

inv

inversion

mar

marker chromosome

mat

maternal origin

minus sign (-)

loss

short arm of chromosome

parentheses

surround structurally altered chromosome and breakpoints

pat

paternal origin

plus sign (+)

gain

long arm of chromosome

question mark
(?)

questionable identification of a chromosome or chromosome

structure

ring chromosome

rec

recombinant chromosome

satellite

sce

sister chromatid exchange

(a chromosome that has lost one of its arms and replaced it with an
exact copy of the other arm)

(a chromosome whose arms have fused together to form a ring;

due to radiation)

ISCN
Symbols

Abbreviated Terms

semicolon (;)

separates altered chromosomes and breakpoints in structural

rearrangements involving more than one chromosome

slant line (/)

separates clones

t
ter
upd

Translocation

(a chromosome abnormality caused by rearrangement of parts

between non-homologous chromosomes; eg between chromosome 8 and
chromosome 14)

terminal (end of chromsome)

uniparental disomy

(occurs when a person receives two copies of a

chromosome, or part of a chromosome, from one parent and no copies from the
other parent)

In situ hybridyzation:
minus sign (-)

absent from a specific chromosome

plus sign (+)

present on a specific chromosome

multiplication
sign (x)

precedes the number of signals seen

period (.)

separates cytogenetic observations from results of in situ

hybridization

semicolon (;)

separates probes on different derivative chromosomes

fish

fluorescence in situ hybridization

ish

in situ hybridization; when used without a prefix, this applies

to chromosomes of dividing cells (metaphase or
prometaphase)

Standard Nomenclature for

Chromosome Karyotypes
46, XX

Total number
of
chromosome
s

Sex
chromosom
es
(male/femal
e)

Standard Nomenclature for

Chromosome Karyotypes
Female
47
chromosome
s

47, XX,+21

Gain one extra copy of

chromosome 21

Female with
trisomy 21, Down
syndrome

Description
Standard Nomenclature
for Chromosome
46,XY
Normal male chromosome constitution
Karyotypes Female with trisomy 21, Down syndrome
47,XX,+21
Karyotype

47,XY,
+21[10]/46,XY[10]

Male who is a mosaic of trisomy 21 cells and normal cells

(10 cells scored for each karyotype)

46,XY,del(4)(p14)

Male with distal and terminal deletion of the short arm of

chromosome 4 from band p14 to terminus

46,XX,dup(5)
(p14p15.3)

Female with a duplication within the short arm of

chromosome 5 from bands p14 to p15.3

45,XY,der(13;14)
(q10;q10)

A male with a balanced Robertsonian translocation of

chromosomes 13 and 14. Karyotype shows that one
normal 13 and one normal 14 are missing and replaced
with a derivative chromosome composed of the long
arms of chromosomes 13 and 14

46,XY,t(11;22)
(q23;q22)

A male with a balanced reciprocal translocation between

chromosomes 11 and 22. The breakpoints are at 11q23
and 22q22

46,XX,inv(3)(p21q13)

An inversion on chromosome 3 that extends from p21 to

q13; because it includes the centromere, this is a
pericentric inversion

46,X,r(X)(p22.3q28)

A female with one normal X chromosome and one ring X

chromosome formed by breakage at bands p22.3 and
q28 with subsequent fusion

46,X,i(Xq)

A female with one normal X chromosome and an

CHROMOSOMAL ABNORMALITIES

Chromosome
Abnormalities
Definition = changes resulting in visible alteration
of the chromosomes
Most chromosomal aberrations are produced by
misrepair of broken chromosomes
improper recombination
malsegregation of chromosomes

during mitosis or meiosis

Types of Chromosomal Abnormality

Constitutional
abnormality
A chromosomal
abnormality which is
present in all cells of
the body
Present very early in
development: result of
an abnormal sperm or
egg
abnormal fertilization
an abnormal event in
the early embryo

Somatic/acquired
abnormality
A chromosomal
abnormality which is
present in only certain
cells or tissues
An individual with a
somatic abnormality is a
mosaic, containing cells
with two different
chromosome
constitutions, with both
cell types deriving from
the same zygote

Types of Chromosomal Abnormality

Mosaics have two or more genetically

different cell lines derived from a single
zygote

Mosaicism

The different types of mosaicism that may be detected by prenatal diagnosis.

A, Generalized mosaicism affecting both the fetus and placenta. B, Confined
placental mosaicism with normal and abnormal cell lineages present. C,
Confined placental mosaicism with only an abnormal cell lineage present. D,
Mosaicism confined to the embryo. (Adapted from Kalousek DK [1994] Current topic:

Mosaicism

 PallisterKillian
syndrome(alsotetrasomy
12p mosaicismorPallister
mosaic aneuploidy
syndrome) is an extremely rare
genetic disorderoccurring
inhumans.
Pallister-Killian occurs due to the
presence of the anomalous
extraisochromosome12p.
An isochromosome is a
chromosome that has lost one of its
arms and replaced it with an exact
copy of the other arm.

This leads to the development

oftetrasomy12p.
Because not all cells have the
extra isochromosome, PallisterKillian is amosaiccondition.

 McCuneAlbright syndrome is
suspected when two of the three
following features are present:
1. (autonomous)endocrinehyper
function such asprecocious puberty
(pubertyoccurring at an unusually
early age)
2. Polyostotic fibrous dysplasia
a form offibrous dysplasiaaffecting more
than one bone

3. UnilateralCaf-au-lait spots
pigmentedbirthmarks.The namecaf au
laitisFrenchfor "coffee with milk" and
refers to their light-brown color.

The asymmetrical skin

pigmentation seen in McCune
Albright syndrome is associated
with mutation of the GNAS1
gene in some but not all cells
(somatic mosaicism).

 Osteogenesis
imperfecta(OIand
sometimes known asbrittle
bone disease, or "Lobstein
syndrome") is a congenital
bone disorder.
In Type II: Collagen is not of
a sufficient quality or
quantity
Most cases die within the first
year of life due torespiratory
failureorintracerebral
hemorrhage
Severerespiratoryproblems
due to underdeveloped lungs
Severe bone deformity and
small stature

Clinical significance of
mosaicism

X chromosome mosaicism

If the proportion of
cytogenetically abnormal cells
in a mosaic is sufficiently
large, that individual will
manifest disease
If the abnormal cells are
proportionally small in
comparison to cytogenetically
normal cells, the normal cells
may be sufficient to prevent
disease or reduce its severity
Eg. Most individuals with
Turner's syndrome that
survive are found to be
mosaics with a substantial

Early in embryogenesis, all but

one X chromosome are
functionally inactivated through a
process called X chromosome
inactivation
Because this inactivation occurs
randomly, all normal females
have roughly equal populations of
two genetically different cell types
and are therefore a type of
mosaic
In roughly half of their cells, the
paternal X chromosome has been
inactivated, and in the other half
the maternal X chromosome is
inactive
Implications in X-linked genetic
diseases

Types of Chromosomal Abnormality

Chromosomal abnormalities, whether constitutional or

somatic, mostly fall into two categories:

Numerical abnormalities
Structural abnormalities

Nomenclature of chromosome
abnormalities
Numerical abnormalities
Triploidy

69,XXX, 69,XXY, 69,XYY

Trisomy

e.g. 47,XX, +21

Monosomy

e.g. 45,X

Mosaicism

e.g. 47,XXX / 46,XX

Structural abnormalities
Deletion

e.g. 46,XY, del(4) (p16.3)a

46,XX, del(5) (q13q33)a

Inversion

e.g. 46,XY, inv(11) (p11p15)

Duplication

e.g. 46,XX, dup(1) (q22q25)

Insertion

e.g. 46,XX, ins(2) (p13q21q31)b

Ring

e.g. 46,XY, r(7) (p22q36)

Marker

e.g. 47,XX, +marc

Translocation, reciprocal

e.g. 46,XX, t(2;6) (q35;p21.3)d

Translocation,

e.g. 45,XY, der(14;21) (q10;q10)e

Robertsonian

46,XX, der(14;21) (q10;q10), +21f

Numerical Chromosomal
Abnormalities
Three classes of numerical chromosomal
abnormalities can be distinguished:
Polyploidy
Triploidy
Tetraploidy

Aneuploidy
Mixoploidy

Polyploidy
Euploid = a cell that contains a multiple of 23
chromosomes in its nucleus
Haploid gametes and diploid somatic cells are
euploid

Euploidy = having complete chromosome sets (n,

2n, 3n, etc)
Polyploidy = the presence of a complete set of
extra chromosomes in a cell
Plants

Polyploidy
In humans:
Triploidy (69 chromosomes in nucleus; 69,XXX)
Tetraploidy (92 chromosomes; 69,XXXX)

Other combinations of the X and Y chromosomes

may be seen
The number of chromosomes present in each of
these conditions is a multiple of 23 the cells are
euploid in each case
BUT, the additional chromosomes encode a large
amount of surplus gene product multiple
anomalies

Polyploidy
Triploidy
1 in 10,000 live births
Accounts for 15% of chromosome abnormalities at
conception spontaneously aborted
Cause fetal loss in the first two trimesters
Triploid fetuses that survive to term die shortly after
birth
Etiology:
Fertilization of an egg by two sperm (dispermy)
The resulting zygote receives 23 chromosomes from the egg and
23 chromosomes from each of the two sperm cells 69
chromosomes

Fusion of an ovum and a polar body, each containing 23

chromosomes, and subsequent fertilization by a sperm cell
Meiotic failure = when a diploid sperm or egg cell, or a triploid
zygote is produced

Dispermy, variants of triploid zygote cleavage and their possible developmental outcomes (A E).

2003 by Oxford University Press

Golubovsky M Hum. Reprod. 2003;18:236-242

Polyploidy
Tetraploidy
Much rarer than triploidy
Only a few live births, and those infants survived
for only a short period
Etiology:
Mitotic failure in the early embryo
All of the duplicated chromosomes migrate to one of
the two daughter cells

Fusion of two diploid zygotes

Polyploidy

Origins of triploidy and tetraploidy

About two-thirds of human triploids arise by fertilization of a single egg by
two sperm (A)
Other causes are a diploid egg (B) or sperm (C)
Most human triploids abort spontaneously; very rarely they survive to
term, but not beyond.
Tetraploidy (D) results from failure of the first mitotic division after
fertilization, and is incompatible with development.

Polyploidy
Cells that have a multiple of 23 chromosomes are
said to be euploid
Triploidy (69 chromosomes) and tetraploidy (92
chromosomes) are polyploid conditions found in
humans
Most polyploid conceptions are spontaneously
aborted, and all are incompatible with long-term
survival.

Aneuploidy
Aneuploid = Cells that contain missing or additional individual
chromosomes (not a multiple of 23 chromosomes; opposite to
euploid)
Usually only one chromosome is affected, but it is possible for more
than one chromosome to be missing or duplicated
Autosomal aneuploidies
most clinically important of chromosome abnormalities
consist primarily of monosomy (the presence of only one copy of a
chromosome in an otherwise diploid cell) and trisomy (three copies of a
chromosome)

1. Autosomal monosomies
incompatible with survival to term, so only a small number of them
have been observed among live-born individuals

2. Trisomies
Some survive
Trisomies produce less-severe consequences than monosomies: the
body can tolerate excess genetic material more readily than it can
tolerate a deficit of genetic material

Aneuploidy
Aneuploid cells arise through two main mechanisms:
1. Nondisjunction

Failure of paired chromosomes to separate (disjoin) in anaphase

of meiosis I, or failure of sister chromatids to disjoin at either
meiosis II or at mitosis

Nondisjunction in meiosis produces gametes with 22 or 24

chromosomes, which after fertilization by a normal gamete
make a trisomic or monosomic zygote

Nondisjunction in mitosis produces a mosaic

2. Anaphase lag

Failure of a chromosome or chromatid to be incorporated into

one of the daughter nuclei after cell division, as a result of
delayed movement (lagging) during anaphase

Chromosomes that do not enter a daughter cell nucleus are lost

Aneuploidy
Meiotic disjunction

In meiotic nondisjunction, two chromosome homologs migrate to

the same daughter cell instead of disjoining normally and
migrating to different daughter cells. This produces monosomic

Aneuploidy
Aneuploid conditions consist primarily of
monosomies and trisomies.
They are usually caused by nondisjunction.
Autosomal monosomies are almost always lethal,
but some autosomal trisomies are compatible
with survival.

Trisomy 21
47,XY,+21 or 47,XX,+21
1 of every 800 to 1000 live births
The most common autosomal aneuploid condition
compatible with survival to term
Produces Down syndrome

Trisomy 21

A, An infant with Down syndrome, illustrating typical features of this disorder:

upslanting palpebral fissures, redundant skin of the inner eyelid (epicanthic fold),
protruding tongue, and low nasal bridge. B, Same girl as in A, 7 years later. Note that
the typical features are present but less obviously expressed.

Trisomy 21

A karyogram of a male with trisomy 21.

Trisomy 21
Trisomy 21, which causes Down syndrome, is the
most common autosomal aneuploidy seen among
live births
The most significant problems include mental
retardation, gastrointestinal tract obstruction,
congenital heart defects, and respiratory
infections
The extra 21st chromosome is usually contributed
by the mother
Mosaicism is seen in 2% to 4% of Down syndrome
cases a milder phenotype

Trisomy 18

47,XY,+18
Edwards syndrome
Second most common autosomal trisomy
1 per 6000 live births
More common at conception
The most common chromosome abnormality
among stillborns with congenital malformations
<5% of trisomy 18 conceptions survive to term

Trisomy 18
A 3-year-old girl with trisomy 18
(Edwards syndrome) with typical
facial features including a narrow
head, short palpebral fissures, and
malformed external ears as well as
characteristic overlapping of the
index finger on top of the middle
finger.
More than 95% of patients with
Edwards syndrome have complete
trisomy 18; only a small
percentage have mosaicism
As in trisomy 21, there is a
significant maternal age effect
Molecular analyses indicate that,
as in trisomy 21, approximately
90% of trisomy 18 cases are the
result of an extra chromosome
transmitted by the mother.

Trisomy 13

47,XY,+13
Patau syndrome
1 of every 10,000 births
Malformation pattern: primarily of oral-facial
clefts, microphthalmia (small, abnormally formed
eyes), and postaxial polydactyly
Malformations of the central nervous system are
often seen, as are heart defects and renal
abnormalities
Cutis aplasia (a scalp defect on the posterior
occiput) can also occur

Trisomy 13
The survival rate is very similar to that of trisomy
18, and almost all live-born infants die during the
first year of life
About 80% of patients with Patau syndrome have
full trisomy 13
Most of the remaining patients have trisomy of the
long arm of chromosome 13 due to a translocation

Maternal age effect

Most conceptions are spontaneously lost during
pregnancy

Trisomy 13

A, Newborn boy with full trisomy 13 (Patau syndrome). This baby has a
cleft palate, atrial septal defect, inguinal hernia, and postaxial
polydactyly of the left hand. B, A boy with full trisomy 13 at age 7 years
(survival beyond the first year is uncommon). He has significant visual

Trisomy 13 & 18
Trisomies of the 13th and 18th chromosomes are
sometimes compatible with survival to term,
although 95% or more of affected fetuses are
spontaneously aborted
These trisomies are much less common at birth
than is trisomy 21, and they produce severer
disease features, with 95% mortality during the
first year of life
As in trisomy 21, there is a maternal age effect,
and the mother contributes the extra
chromosome in approximately 90% of cases.

Trisomies, Nondisjunction, and

Maternal Age
Nearly all autosomal
trisomies increase
with maternal age
as a result of
nondisjunction in
older mothers
There is little
evidence for a
paternal age effect
on nondisjunction in
males

The prevalence of Down syndrome among

live births in relation to age of the mother.
The prevalence increases with maternal
age and becomes especially notable after
the age of 35 years. (Data from Hook EB,
Chambers GM: Birth defects.
1977;23[3A]:123-141.)

Sex Chromosome
Aneuploidy
Among live-born infants, about 1 in 400 males and
1 in 650 females have some form of sex
chromosome aneuploidy
Due to X inactivation
Consequences are less severe than those of
autosomal aneuploidy
Almost all are compatible with survival, except in
the absence of an X chromosome

Monosomy of the X Chromosome

(Turner Syndrome)
45,X
Turner syndrome
Female
Characteristic
phenotype: short
stature, sexual
infantilism and
ovarian
dysgenesis, and
a pattern of
major and minor
malformations

A girl with Turner syndrome (45,X). Note the

characteristically broad, webbed neck. Stature is
reduced, and swelling (lymphedema) is seen in the

Monosomy of the X Chromosome

(Turner Syndrome)
Variations in chromosomal abnormality
in Turner syndrome:
About 50% of these patients have a
45,X karyotype in their peripheral
lymphocytes
At least 30% to 40% have mosaicism,
most commonly 45,X/46,XX and less
commonly 45,X/46,XY
Mosaics who have Y chromosomes in
some cells are predisposed to neoplasms
(gonadoblastomas) in the gonadal streak
tissue

About 10% to 20% of patients with

Turner syndrome have structural X
chromosome abnormalities involving a
deletion of some or all of Xp

Karyotype variations in Turner Syndrome

45,X
45,X/46,
XX
45,X/46,
XY

Monosomy of the X Chromosome

(Turner Syndrome)
Approximately 60% to 80% of monosomy X cases
are caused by the absence of a paternally derived
sex chromosome, occurring either during early
mitosis in the embryo or during meiosis in the
father (i.e., the offspring receives an X
chromosome only from the mother)
The 45,X karyotype is estimated to occur in 1% to
2% of conceptions, but Turner syndrome is seen
in only about 1/2000 to 1/3000 live-born girls
Most 45,X conceptions are lost prenatally

Monosomy of the X Chromosome

(Turner Syndrome)
Among those that do survive to term, many are chromosomal
mosaics, and mosaicism of the placenta alone (confined placental
mosaicism) is especially common
Fetal survival due to the presence of some normal cells in mosaic
fetuses
Etiology: Mutations in the SHOX gene, which encodes a transcription
factor expressed in embryonic limbs, produce short stature
SHOX is ocated on the distal tip of the X and Y short arms (in a region of
the X chromosome that escapes inactivation
Normally transcribed in two copies in both males and females
In females with Turner syndrome, this gene would be present in only one
active copy, and the resulting haploinsufficiency contributes to short
stature.

Klinefelter Syndrome
47,XXY
1/500 to 1/1000 male births
Common cause of primary hypogonadism in
males
Characteristics:
Most patients with Klinefelter syndrome are sterile
as a result of atrophy of the seminiferous tubules
Testosterone levels in adolescents and adults are low
Gynecomastia (breast development) is seen in
approximately one third of affected persons and
leads to an increased risk of breast cancer, which
can be reduced by mastectomy (breast removal)

Klinefelter Syndrome
In about 50% of Klinefelter cases, the extra X
chromosome is derived maternally
Syndrome increases in incidence with
advanced maternal age
15% of patients have mosaicism increases
the likelihood of viable sperm production
48,XXXY and 49,XXXXY karyotypes have also
been reported
Because they have a Y chromosome, they have a
male phenotype, but the degree of mental
deficiency and physical abnormality increases with
each additional X chromosome

Klinefelter Syndrome
A male with Klinefelter
syndrome (47,XXY).
Stature is increased,
gynecomastia may be
present, and body
shape may be
somewhat feminine. (From
McKusick VA: J Chronic Dis 1960; 12-1-202.)

Trisomy X

47,XXX
1/1000 females
Usually has benign consequences
These females sometimes suffer from sterility,
menstrual irregularity, or mild mental retardation
90% of cases are the result of nondisjunction in
the mother
Have maternal age effect
Females have also been seen with four, five, or
even more X chromosomes
Each additional X chromosome is accompanied by
increased mental retardation and physical
abnormality

47,XYY Syndrome

47,XYY
Males
Taller than average
Have a 10- to 15-point reduction in average IQ
Incidence in the male prison population was
discovered to be as high as 1/30, compared with
1/1000 in the general male population
However, according to research, XYY males are not
inclined to commit violent crimes
Only increased incidence of minor behavioral
disorders, ie. hyperactivity, attention deficit disorder,
and learning disabilities.

Structural Chromosomal
Abnormalities
In addition to the loss or gain of whole
chromosomes, parts of chromosomes can be lost
or duplicated as gametes are formed, and the
arrangement of portions of chromosomes can be
altered
Types:
1.

Unbalanced (the rearrangement causes a gain or

loss of chromosomal material)

2.

can produce serious disease in individuals or their

offspring

Balanced (the rearrangement does not produce a

loss or gain of chromosome material)
often do not produce serious health consequences.

Structural Chromosomal
Abnormalities
Occur when homologous chromosomes line up
improperly during meiosis (e.g., unequal
crossover)
In addition, chromosome breakage can occur
during meiosis or mitosis
Sometimes, the breaks remain, or they heal in a
fashion that alters the structure of the chromosome

Structural Chromosomal
Abnormalities

Translocations
Deletions
Rearrangements
UPD
Duplications
Ring chromosomes
Inversions
Isochromosomes

Translocations
Definition = the interchange of genetic
material between nonhomologous
chromosomes (chromosomes which are not
the same length, centromere position and
staining pattern)
Balanced translocations
Most common
1 of every 500 to 1000 individuals
Two basic types of translocations
Reciprocal
Robertsonian

Reciprocal Translocations
Happen when breaks occur in two different
chromosomes and the material is mutually
exchanged derivative chromosomes (der)
Carrier is usually unaffected because he or she
has a normal complement of genetic material
However, the carrier's offspring can either
Be normal
Carry the translocation
Have duplications or deletions of genetic material

Prevalence of Chromosomal Abnormalities among

Newborns
Abnormality

Prevalence at Birth

Autosomal Syndromes
Trisomy 21

1/800

Trisomy 18

1/6000

Trisomy 13

1/10,000

Unbalanced rearrangements

1/17,000

Balanced Rearrangements
Robertsonian translocations

1/1000

Reciprocal translocations

1/11,000

Prevalence of Chromosomal Abnormalities among

Newborns
Abnormality

Prevalence at Birth

Sex Chromosome Abnormalities

47,XXY

1/1000 male births

47,XYY

1/1000 male births

45,X*

1/5000 female births

47,XXX

1/1000 female births

All Chromosome Abnormalities

Autosomal disorders and
unbalanced rearrangements

1/230

Balanced rearrangements

1/500*

*The 45,X karyotype accounts for about half of the cases of Turner syndrome.

Reciprocal Translocation
A, The parent has a
reciprocal balanced
translocation involving the
short arms of
chromosomes 6 and 3
The distal short arm of the
6 has been translocated to
the very distal tip of the 3
A small piece of
chromosome 3 is attached
to the derivative 6
This person had a child
whose chromosomes are
depicted in B

Reciprocal Translocation
B. From one parent, the
child received the
derivative chromosome 3
(with part of the 6 short
arm attached) and the
normal 6
From the other parent, the
child received a normal 3
and a normal 6
Therefore, the child had a
partial trisomy of the 6
short arm and,
presumably, a small
deletion of the 3 short arm

Reciprocal Translocations
If the translocations occur at 3p13 and 6p14, the
karyotype is designated 46,XX,t(3;6)(p13;p14)
The offspring of this woman received the derivative
chromosome 3, termed der(3), and the normal 6;
thus, the child had a partial trisomy of the distal
portion of chromosome 6 (i.e., 6p trisomy)

This is a well-established but rather uncommon

chromosomal syndrome.

Robertsonian
Translocations
In Robertsonian translocations
The short arms of two non-homologous chromosomes
are lost
The long arms fuse at the centromere to form a single
chromosome

Involve only acrocentric chromosomes (13, 14, 15,

21, and 22)
This is because the short arms of these chromosomes
are very small and contain no essential genetic material

Carriers of Robertsonian translocations lose no

essential genetic material phenotypically normal,
but have only 45 chromosomes in each cell
Their offspring, however, may inherit an extra or
missing long arm of an acrocentric chromosome

Robertsonian
Translocations
In a Robertsonian
translocation, the long
arms of two
acrocentric
chromosomes fuse,
forming a single
chromosome

Robertsonian
Translocation
Commonly involves fusion of the long arms of
chromosomes 14 and 21
The karyotype of a male carrier of this
translocation is 45,XY,der(14;21)(q10;q10)
This person lacks one normal 14 and one normal 21
Instead, he has a chromosome derived from a
translocation of the entire long arms of
chromosomes 14 and 21

There are a number of possible segregation

patterns for the gametes formed by a carrier
of a Robertsonian translocation

Robertsonian
Translocation
Alternate segregation
1. quadrant a alone, or
2. quadrant b with
quadrant c
. produces either a normal
chromosome
constitution or a
translocation carrier with
a normal phenotype

Robertsonian
Translocation
If alternate segregation occurs, then the offspring
are either
chromosomally normal, or
have a balanced translocation with a normal
phenotype

Robertsonian Translocation
Adjacent segregation
1.

quadrant a with b,

2.

quadrant c alone,

3.

quadrant a with c, or

4.

quadrant b alone

. produces unbalanced gametes and

results in conceptions with
translocation
1.

Down syndrome,

2.

monosomy 21,

3.

trisomy 14, or

4.

monosomy 14, respectively

Eg. monosomy 14 is produced when

the parent who carries the
translocation transmits a copy of
chromosome 21 but does not
transmit a copy of chromosome 14

Robertsonian
Translocation
If one of the adjacent segregation patterns
occurs:
The gametes are unbalanced
The offspring may have
Fetuses do not survive to
trisomy 14
term
monosomy 14
Fetus results in three copies of 21q and a Down syndrome
monosomy 21, or phenotype
trisomy 21:
genetically the same as trisomies and monosomies
produced by nondisjunction

Robertsonian translocations are responsible

for approximately 5% of Down syndrome
cases.

Robertsonian
Translocation
It is expected that the three types of conceptions
compatible with survival would occur in equal
frequencies:
1. 1/3 would be completely normal
2. 1/3 would carry the translocation but be
phenotypically normal
3. 1/3 would have Down syndrome

Deletions
Deletions involve loss of a chromosome segment,
resulting in chromosome imbalance
A carrier of a chromosomal deletion (with one normal
homologue and one deleted homologue) monosomic
for the genetic information on the corresponding
segment of the normal homologue
Clinical consequences haploinsufficiency
The inability of a single copy of the genetic material to
carry out the functions normally performed by two copies
Depend on size of the deleted segment, and number and
function of the genes that it contains

1 in 7000 live births

Deletions
Two types:
1.

Terminal deletion: a deletion at the end of a

chromosome

2.

Interstitial deletion: a deletion along a chromosome

arm

Etiology:
. Chromosome breakage
. Loss of the acentric segment
. Unequal crossing over between misaligned
homologous chromosomes or sister chromatids
. Abnormal segregation of a balanced translocation or
inversion

chromosomes.
A, Terminal and
interstitial deletions, each
generating an acentric
fragment.
B, Unequal crossing over
between segments of
homologous
chromosomes or between
sister chromatids
(duplicated or deleted
segment indicated by the
brackets).
C, Ring chromosome with
two acentric fragments.
D, Generation of an
isochromosome for the
long arm of a
chromosome.
E, Robertsonian
translocation between
two acrocentric
chromosomes.
F, Insertion of a segment
of one chromosome into a
nonhomologous
chromosome.

Deletions

Deletions

Two-color FISH analysis of proband with

DiGeorge syndrome, demonstrating
deletion of 22q11.2 on one homologue.
Green signal is hybridization to a control
probe in distal chromosome 22q.
Red signal on proximal 22q is a singlecopy probe for a region that is present on
one chromosome 22 but deleted from the
other (arrow). (Courtesy of Hutton Kearney, Duke

FISH detection of a terminal deletion of

chromosome 1p by use of subtelomeric
probes for 1p (green) and 1q (red).
Arrow indicates the 1p deletion. (Courtesy of
Leah Stansberry and Hutton Kearney, Duke University
Medical Center.)

Deletions
A well-known example: Cri-duchat syndrome
Cri-du-chat syndrome is
caused by a deletion of the
distal short arm of
chromosome 5; 46,XY,del(5p)
1 in 50,000 live births
Clinical characteristics: mental
retardation (average IQ about
35), microcephaly (small head)
Many persons with cri-du-chat
syndrome now survive to
adulthood

Clinical features of a patient with

Cri du Chat syndrome at age of 8
months (A), 2 years (B), 4 years (C)
and 9 years (D)

Deletions
Another example: WolfHirschhorn syndrome
Caused by a deletion of the
distal short arm of chromosome
4
Other well-known deletions
involve 18p, 18q, and 13q
18p deletion syndrome: clinical
features are more subtle
recognized when chromosome
analysis is performed for
evaluation of developmental
disability
18q and 13q are more distinctive
diagnosis can be made before
karyotype is obtained

Child with Wolf-Hirschhorn

syndrome (46,XX,del[4p]). Note the
wide-spaced eyes and repaired cleft
lip.

Microdeletion Syndromes
Example: Prader-Willi
syndrome
Caused by a small
deletion of
chromosome 15q11q13 (50% of patients)
In total, about 70% of
Prader-Willi cases are
caused by
microdeletions of 15q

Due to imprinting, the

inheritance of a microdeletion
of the paternal chromosome
15 material produces PraderWilli syndrome, while a
microdeletion of the
maternally derived
chromosome 15 produces the
phenotypically distinct
Angelman syndrome
Imprinted alleles are silenced
such that the genes are either
expressed only from the nonimprinted allele inherited from
the mother, or in other instances
from the non-imprinted allele
inherited from the father

Microdeletion Syndromes

Inheritance of the deletion from

the father produces Prader-Willi
syndrome.
Note the inverted V-shaped upper

Inheritance of the deletion from the

mother produces Angelman
syndrome, characterized by severe
mental retardation, seizures, and an

Microdeletion Syndromes
Another example: Williams
syndrome
Clinical characteristics:
mental retardation,
supravalvular aortic
stenosis (SVAS), multiple
peripheral pulmonary
arterial stenoses
Facial features: dental
malformations and
hypercalcemia

Etiology:
Mutations or deletions of elastin
Elastin is an important component
of the aortic wall
Result in isolated SVAS without the
other features of Williams syndrome

Larger deletions, encompassing

additional genes
produce the complete Williams
syndrome phenotype.

Deletion of LIMK1
This gene encodes a brainexpressed kinase that may be
involved in the visual-spatial
cognition defects observed in
patients with Williams syndrome.

Partial deletions of the critical

region affecting only the ELN and
LIMK1 genes
These persons have SVAS and
visual-spatial cognitive deficiency
but none of the other features of
Williams syndrome

Microdeletion Syndromes

A, Girl with Williams syndrome, illustrating typical facial features: broad forehead,
short palpebral fissures, low nasal bridge, anteverted (upturned) nostrils, long
philtrum, full cheeks, and relatively large mouth with full lips.
B, Angiogram illustrating supravalvular aortic stenosis (narrowing of the
ascending aorta) (arrow). (Courtesy Dr. Mark Keating, Harvard University.)

Microdeletion Syndromes*
Syndrome

Clinical Features

Chromosomal
Deletion

Prader-Willi

Mental retardation, short stature,

obesity, hypotonia, characteristic
facies, small feet

15q11-13

Angelman

Mental retardation, ataxia,

uncontrolled laughter, seizures

15q11-13

Langer-Giedion

Characteristic facies, sparse hair,

exostosis, variable mental
retardation

8q24

Miller-Dieker

Lissencephaly, characteristic facies

17p13.3

Velocardiofacial/DiGeo Characteristic facies, cleft palate,

rge
heart defects, poorly developed
thymus

22q11

Smith-Magenis

Mental retardation, hyperactivity,

dysmorphic features, selfdestructive behavior

17p11.2

Williams

Developmental disability,
characteristic facies, supravalvular
aortic stenosis

7q1

Microdeletion Syndromes*
Syndrome

Clinical Features

Chromosomal
Deletion

Deletion 1p36

Mental retardation,
seizures, hearing loss,
heart defects, growth
failure, distinctive facial
features

1p36

Rubinstein-Taybi

Mental retardation,
16p13.3
broad thumbs and great
toes, characteristic facial
features, vertebral and
sternal abnormalities,
pulmonary stenosis

Alagille

Neonatal jaundice,
20p12
"butterfly" vertebrae,
pulmonic valvular
*For most of these conditions,
only some
cases are caused by the listed
stenosis,
characteristic
microdeletion; other cases facial
may be
caused by single-gene mutations within
features
the same region.

Subtelomeric
Rearrangements
Subtelomeric rearrangements involve
deletions or duplications of DNA in the generich regions near telomeres
Can be detected by hybridizing specifically
designed FISH probes to metaphase
chromosomes or by CGH of patient and
control DNA to microarrays containing
subtelomeric probes.
5% of unexplained cases of mental
retardation caused by subtelomeric
rearrangements

Subtelomeric
Rearrangements
Most common: deletion
of several thousand
bases of chromosome
1p36, or monosomy
1p36 syndrome
1 in 5000 live births
Clinical characteristics:
mental retardation,
developmental delay,
seizures, hearing
impairment, heart
defects, hypotonia
(weakness)

Face of young boy with 1p36 deletion

syndrome. Note the horizontal
eyebrows, deep-set eyes, broad nasal
root, and pointed chin.

Uniparental Disomy
Uniparental disomy (UPD) = a condition in which one
parent has contributed two copies of a chromosome,
while the other parent contributed no copies
Contribute to 30% of Prader-Willi cases
UPD can involve
isodisomy (meiosis II error), or
heterodisomy (meiosis I error)

UPD can occur as a random event during

gametogenesis or may happen in early embryogenesis
Eg. chromosome loss with subsequent duplication of the
homologous chromosome

It can also occur during trisomic rescue

Uniparental Disomy
Heterodisomic UPD = When the child receives
two (different) homologous chromosomes
(inherited from both grandparents) from one
parent
Isodisomic UPD = When the child receives
two (identical) replica copies of a single
homolog of a chromosome
Isodisomy can result in autosomal recessive disease in the
offspring of a heterozygous parent if the parent
contributes two copies of the chromosome homolog that
contains the disease-causing mutation.

Uniparental Disomy
A trisomic conception can lose one of the
extra chromosomes resulting in an embryo
that has two copies of the chromosome
contributed by one parent
Disomy can also result from the union of a
gamete that contains two copies of a specific
chromosome with a gamete that contains no
copies of that chromosome
In addition to the Prader-Willi and Angelman
syndromes and cystic fibrosis, UPD has been
seen in cases of Russell-Silver syndrome,
hemophilia A, and Beckwith-Wiedemann
syndrome

Uniparental Disomy

Two mechanisms that can produce uniparental disomy.

A, Paternal nondisjunction produces a sperm cell with two copies of a specific
chromosome, and maternal nondisjunction produces an ovum with no copies of
the same chromosome. The resulting zygote has two copies of the father's
chromosome and no copies of the mother's chromosome (in this example the
father contributes both chromosomes, but it is also possible that the mother
could contribute both chromosomes).

Uniparental Disomy

Two mechanisms that can produce uniparental disomy.

B, Nondisjunction (in the mother, in this example) results in a trisomic
zygote. Loss of the paternal chromosome during mitosis produces
embryonic cells that have two copies of the mother's chromosome.

Duplications
Etiology:
Unequal crossing over during meiosis
X-linked color vision loci
Charcot-Marie-Tooth disease

Abnormal segregation from meiosis in a

carrier of a translocation or inversion

Tend to produce less-serious

consequences than deletions
Example: duplication of all or a
portion of chromosome 12p
Pallister-Killian syndrome
Clinical characteristics: mental
retardation, and birth defects related to
trisomy or tetrasomy for specific genes

A mosaic tetrasomy 12p. Note

the high foreheads, sparse hair
on the temple, a wide space
between the eyes, epicanthal
folds, and a flat nose.
The epicanthic fold is
the skin fold of the
upper eyelid covering
the inner corner of the

Duplicatio
ns
Structural rearrangements of
chromosomes.
A, Terminal and interstitial
deletions, each generating an
acentric fragment.
B, Unequal crossing over between
segments of homologous
chromosomes or between sister
chromatids (duplicated or deleted
segment indicated by the
brackets).
C, Ring chromosome with two
acentric fragments.
D, Generation of an
isochromosome for the long arm of
a chromosome.
E, Robertsonian translocation
between two acrocentric
chromosomes.
F, Insertion of a segment of one
chromosome into a
nonhomologous chromosome.

Ring Chromosomes
Ring chromosome =
chromosome whose arms
have fused together to form a
ring
Deletions sometimes occur at
both tips of a chromosome
The remaining chromosome ends
can then fuse, forming a ring
chromosome

Karyotype in female: 46,X,r(X)

Often lost monosomy for
the chromosome in some cells
(mosaicism for the ring
chromosome)

Both tips of a chromosome can be

lost, leaving sticky ends that attach
to each other, forming a ring
chromosome. A chromosome 12 ring

Ring
chromosomes
Structural rearrangements of
chromosomes.
A, Terminal and interstitial
deletions, each generating an
acentric fragment.
B, Unequal crossing over between
segments of homologous
chromosomes or between sister
chromatids (duplicated or deleted
segment indicated by the
brackets).
C, Ring chromosome with two
acentric fragments.
D, Generation of an
isochromosome for the long arm of
a chromosome.
E, Robertsonian translocation
between two acrocentric
chromosomes.
F, Insertion of a segment of one
chromosome into a
nonhomologous chromosome.

Inversions
An inversion is the result of two breaks on a
chromosome followed by the reinsertion of
the intervening fragment at its original site
but in inverted order
Thus, a chromosome symbolized as ABCDEFG might
become ABEDCFG after an inversion

Pericentric inversion = Inversion includes

centromere
Paracentric inversions = Inversions that do
not involve centromere
Like reciprocal translocations, inversions are a

Inversions
Inversions can interfere with meiosis
chromosome abnormalities in the offspring of
inversion carriers
Because chromosomes must line up in perfect
order during prophase I, a chromosome with an
inversion must form a loop to line up with its
normal homolog
Crossing over within this loop can result in duplications or
deletions in the chromosomes of daughter cells
Thus, the offspring of persons who carry inversions often
have chromosome deletions or duplications

1 in 1000 people carries an inversion at risk for

Inversions
Example of a pericentric
inversion on chromosome 8
(46,XX,inv[8])
5% of the offspring of
persons who carry this
inversion receive a deletion
or duplication of the distal
portion of 8q
This combination results in
the recombinant 8 syndrome
A pericentric inversion in chromosome 8
causes the formation of a loop during the
alignment of homologous chromosomes in
meiosis. Crossing over in this loop can
produce duplications or deletions of
chromosome material in the resulting
gamete. The offspring (lower right) received

Characterized by mental
retardation, heart defects,
seizures, and a characteristic
facial appearance.

Inversions
dicentric
acentric

norma balance
l
d

unbalanc
ed

deficien
cy

duplicatio
n with
Crossing over within inversion loops formed at meiosis I in carriers of a chromosome
segment B-C inverted (order A-C-B-D, instead of A-B-C-D). A, Paracentric inversion. Gametes
formed after the second meiosis usually contain either a normal (A-B-C-D) or a balanced (A-CB-D) copy of the chromosome because the acentric and dicentric products of the crossover
are inviable. B, Pericentric inversion. Gametes formed after the second meiosis may be
normal, balanced, or unbalanced. Unbalanced gametes contain a copy of the chromosome

Isochromosomes
An isochromosome is a chromosome in which one arm is
missing and the other duplicated in a mirror-image fashion
Isochromosomes of most autosomes are lethal
Due to alteration of genetic material
Mostly involve the X chromosome
Babies with isochromosome Xq (46,X,i[Xq]) usually have
features of Turner syndrome
Isochromosome 18q produces an extra copy of the long
arm of chromosome 18
Infants with Edwards syndrome
Can be due to Robertsonian translocations of homologous
acrocentric chromosomes (e.g., a Robertsonian translocation
of the two long arms of chromosome 21)

Isochromosomes
Top, Normal chromosome
division.
Center, An isochromosome
is formed when a
chromosome divides along
an axis perpendicular to its
usual axis of division. This
produces one chromosome
with only the short arms
and another with only the
long arms.
Bottom, A normal X
chromosome is compared
with an isochromosome of
Xq.

Isochromosomes
Structural rearrangements of
chromosomes.
A, Terminal and interstitial
deletions, each generating an
acentric fragment.
B, Unequal crossing over between
segments of homologous
chromosomes or between sister
chromatids (duplicated or deleted
segment indicated by the
brackets).
C, Ring chromosome with two
acentric fragments.
D, Generation of an
isochromosome for the long arm of
a chromosome.
E, Robertsonian translocation
between two acrocentric
chromosomes.
F, Insertion of a segment of one
chromosome into a
nonhomologous chromosome.

 Chromosome abnormalities