Chromosome Mutations:

Variation in Number and

Arrangement

Variation in chromosome number.

Structural variations of Chromosomes - deletions,
duplications, inversions, translocations, fragile sitess.
Aneuploidy, polyploidy. Monosomy; Trisomy
CHROMOSOME ABNORMALITIES
Abnormalities of chromosomes may be :
Numerical or Structural;
Involve :
One or more autosomes, sex chromosomes, or both
simultaneously.
CHROMOSOME ABNORMALITIES
The overall incidence of chromosome abnormalities is
approximately 1 in 154 live births.
CHROMOSOME ABNORMALITIES
By far the most common type of clinically significant
chromosome abnormality is aneuploidy:
An abnormal chromosome number due to an extra or
missing chromosome.
An aneuploid karyotype is always associated with
physical or mental abnormalities or both.

Structural abnormalities (rearrangements involving one

or more chromosomes) are also relatively common.
CHROMOSOME ABNORMALITIES

Chromosome abnormalities are described by a

standard set of abbreviations and nomenclature that
indicathe nature of the abnormality;

 In the case of analyses performed by FISH or

microarrays- the technology used.
Gene Dosage, Balance and Imbalance
For chromosome and genomic disorders, it is the
quantitative aspects of gene expression that underlie
disease;

The clinical consequences of any particular chromosome

abnormality will depend on:
The resulting imbalance of parts of the genome;
The specific genes contained in or affected by the
abnormality;
The likelihood of its transmission to the next
generation.
Gene Dosage, Balance and Imbalance

Most genes in the human genome are present in two

doses and are expressed from both copies.
Some genes, however, are expressed from only a single
copy :
(e.g., imprinted genes and X-linked genes subject to X
inactivation);

Extensive analysis of clinical cases has demonstrated

that the relative dosage of these genes is critical for
normal development.
Gene Dosage, Balance and Imbalance
One or three doses instead of two is generally not
conducive to normal function for a gene or set of genes
that are typically expressed from two copies.

Similarly, abnormalities of genomic imprinting or X

inactivation that cause the anomalous expression of
two copies of a gene or set of genes instead of one
invariably lead to clinical disorders.
Abnormalities of Chromosome
Number
A chromosome complement with any chromosome
number other than 46 is said to be heteroploid.

An exact multiple of the haploid chromosome number

(n) is called euploid;
Any other chromosome number is aneuploid.
UNBALANCED KARYOTYPES AND GENOMES IN LIVEBORNS:
GENERAL GUIDELINES FOR COUNSELING

Monosomies are more deleterious than trisomies.

Complete monosomies are generally not viable,
Except for monosomy for the X chromosome.

Complete trisomies are viable for chromosomes 13, 18,

21, X, and Y.
UNBALANCED KARYOTYPES AND GENOMES IN
LIVEBORNS: GENERAL GUIDELINES FOR COUNSELING

The phenotype in partial aneuploidy depends on a

number of factors, including :

The size of the unbalanced segment, which regions of

the genome are affected ;
Which genes are involved;
Whether the imbalance is monosomic or trisomic.
 UNBALANCED KARYOTYPES AND GENOMES IN
LIVEBORNS: GENERAL GUIDELINES FOR COUNSELING
Risk in cases of inversions depends on :
1. the location of the inversion with respect to the
centromere;
2. the size of the inverted segment.

For inversions that do not involve the centromere

(paracentric inversions), there is a very low risk for an
abnormal phenotype in the next generation.
For inversions that do involve the centromere (pericentric
inversions), the risk for birth defects in offspring may be
significant and increases with the size of the inverted
segment.
 UNBALANCED KARYOTYPES AND GENOMES IN
LIVEBORNS: GENERAL GUIDELINES FOR COUNSELING

For a mosaic karyotype involving any chromosome

abnormality, all bets are off!

Counseling is particularly challenging because the degree

of mosaicism in relevant tissues or relevant stages of
development is generally unknown.
Thus there is uncertainty about the severity of the
phenotype.
 Triploidy and Tetraploidy
In addition to the diploid (2n) number characteristic of
normal somatic cells, two other euploid chromosome
complements:
Triploid (3n)
Tetraploid (4n)
are occasionally observed in clinical material.

Triploidy is observed in 1% to 3% of recognized

conceptions; triploid infants can be liveborn, although
they do not survive long.
 Triploidy and Tetraploidy

The few survive at least to the end of the first

trimester of pregnancy;

 Most result from fertilization of an egg by two sperm

(dispermy).
Other cases result from failure of one of the meiotic
divisions in either sex, resulting in a diploid egg or
sperm.
 Triploidy and Tetraploidy
The phenotypic manifestation of a triploid karyotype
depends on the source of the extra chromosome set;

Triploids with an extra set of maternal chromosomes are

typically aborted spontaneously early in pregnancy;
Those with an extra set of paternal chromosomes typically
have an abnormal degenerative placenta (resulting in a so-
called partial hydatidiform mole), with a small fetus.

Tetraploids are always 92,XXXX or 92,XXYY and likely result

from failure of completion of an early cleavage division of the
zygote.
 Aneuploidy
Aneuploidy is the most common and clinically
significant type.
5% of all clinically recognized pregnancies.
Trisomy- 3 pair of a particular chromosome;
Monosomy- only one representative of a particular
chromosome;
Severe phenotypic consequences;
Aneuploidy
Most common type:
Trisomy 21- Down syndrome;
Trisomy 18 and trisomy 13;
The lowest number of genes located on them!
Trisomy for autosomes with a greater number of genes
is lethal in most instances;
Monosomy for an entire chromosome is almost always
lethal;
An important exception is monosomy for the X
chromosome- Turner syndrome.
 Aneuploidy
The most common chromosomal mechanism :
Meiotic nondisjunction
failure of a pair of chromosomes to disjoin properly during one
of the two meiotic divisions.

The genomic consequences of nondisjunction during meiosis I

and meiosis II are different.
The error occurs during meiosis I-the gamete with 24
chromosomes contains both the paternal and the maternal
members of the pair.
During meiosis II-the gamete with the extra chromosome
contains both copies of either the paternal or the maternal
The different consequences of nondisjunction
 Aneuploidy
Premature separation of sister chromatids in meiosis
I instead of meiosis II.
If this happens, the separated chromatids may by chance
segregate to the oocyte or to the polar body, leading to an
unbalanced gamete.

Nondisjunction can also occur in a mitotic division after

formation of the zygote.
If this happens at an early cleavage division, clinically
significant mosaicism may result.
In some malignant cell lines and some cell cultures, mitotic
nondisjunction can lead to highly abnormal karyotypes.
 Abnormalities of Chromosome Structure
Unbalanced rearrangements are detected in approximately 1
in 1600 live birth;
Deletion or duplication of multiple genes / both;
Duplication of part of a chromosome- Partial trisomy for
the genes within that segment;
Deletion- Partial monosomy;

A broad range of phenotypes can result.

Large structural rearrangements- karyotyping;
Detection of smaller changes- higher resolution analysis,
FISH or chromosomal microarray analysis.
 Deletions and Duplications
Deletions involve loss of a chromosome segment;
Chromosome imbalance
 A carrier of a chromosomal deletion (one normal
homologue /one deleted homologue) is monosomic for
the genetic information on the corresponding segment of
the normal homologue.

Haploinsufficiency:
the inability of a single copy of the genetic material to
carry out the functions normally performed by two
copies.
 Deletions
Cytogenetically visible autosomal deletions have an
incidence of approximately 1 in 7000 live births.

Smaller, submicroscopic deletions detected by microarray

analysis are much more common;
The clinical significance of many such variants has yet to be
fully determined.

 Numerous deletions have been identified in the course of

prenatal diagnosis or in the investigation of dysmorphic
patients or patients with intellectual disability.
 Deletions
A deletion at the end of a chromosome- Terminal;
 Along a chromosome arm- Interstitial;
Deletions may originate simply by chromosome breakage
and loss of the acentric segment.
 Duplications
Duplication appears to be less harmful than deletion.
However, because duplication in a gamete results in
chromosomal imbalance (i.e., partial trisomy), and
because the chromosome breaks that generate it may
disrupt genes, duplication often leads to some phenotypic
abnormality.
 Marker Chromosomes
Very small, unidentified chromosomes, called marker
chromosomes;
Occasionally seen in chromosome preparations, frequently
in a mosaic state.
They are usually in addition to the normal chromosome
complement;
Referred to as supernumerary chromosomes or extra
structurally abnormal chromosomes.

The prenatal frequency of de novo supernumerary marker

chromosomes has been estimated to be approximately 1 in
2500.
 Marker Chromosomes
Larger marker chromosomes contain genomic material
from one or both chromosome arms:
 An imbalance for whatever genes are present.

Depending on the origin of the marker chromosome, the

risk for a fetal abnormality can range from very low to
100%.

For reasons not fully understood, a relatively high proportion

of such markers derive from chromosome 15 and from the
sex chromosomes.
 Ring chromosomes
Many marker chromosomes lack telomeres and are ring
chromosomes;
Formed- when a chromosome undergoes two breaks
and the broken ends of the chromosome reunite in a ring
structure.
Ring chromosomes
Rings experience difficulties at mitosis;
When the two sister chromatids of the ring chromosome
become tangled in their attempt to disjoin at anaphase.

There may be breakage of the ring followed by fusion,

larger and smaller rings may thus be generated.

Because of this mitotic instability, it is not uncommon for

ring chromosomes to be found in only a proportion of cells.
 Isochromosomes
One arm is missing and the other duplicated in a
mirror-image fashion.
A person with 46 chromosomes carrying an isochromosome
has:
 A single copy of the genetic material of one arm (partial
monosomy);
 Three copies of the genetic material of the other arm
(partial trisomy).
Isochromosomes
Isochromosomes for a number of autosomes have been
described;

The most common isochromosome involves the long

arm of the X chromosome— designated i(X) (q10)—in
a proportion of individuals with Turner syndrome;

Frequently seen in karyotypes of both solid tumors and

hematological malignant neoplasms.
 Dicentric Chromosomes
Rare type of abnormal chromosome;
Two chromosome segments, each with a centromere, fuse end
to end.

Dicentric chromosomes, despite their two centromeres, can be

mitotically stable:
1. if one of the two centromeres is inactivated epigenetically;
2. if the two centromeres always coordinate their movement to
one or the other pole during anaphase.

Such chromosomes are formally called pseudodicentric.

The most common pseudodicentrics involve :
The sex chromosomes or the acrocentric chromosomes (so-called
Robertsonian translocations; )
 Balanced Rearrangements
Found in as many as 1 in 500 individuals;
Do not usually lead to a phenotypic effect;
 All the genomic material is present, even though it is
arranged differently.

Important to distinguish here between truly balanced

rearrangements and those that appear balanced
cytogenetically but are really unbalanced at the molecular
level.
Balanced Rearrangements
Because of the high frequency of copy number
polymorphisms around the genome ,
collectively adding up to differences of many
megabases between genomes of unrelated
individuals,
the concept of what is balanced or unbalanced is
subject to ongoing investigation and continual
refinement.
 Balanced Rearrangements
Even when structural rearrangements are truly balanced,
They can pose a threat to the subsequent generation,
Because carriers are likely to produce a significant
frequency of unbalanced gametes.
Therefore have an increased risk for having abnormal
offspring with unbalanced karyotypes;

Depending on the specific rearrangement, that risk can

range from 1% to as high as 20%.
 Balanced Rearrangements
There is also a possibility that one of the chromosome
breaks will disrupt a gene, leading to mutation.

Whole-genome sequencing to examine the nature of

apparently balanced rearrangements in patients who present
with significant phenoypes;
this is an increasingly well-documented cause of disorders in
carriers of balanced translocations
 such translocations can be a useful clue to the
identification of the gene responsible for a particular
genetic disorder.
 Translocations
Translocation involves the exchange of chromosome
segments between two chromosomes.

There are two main types:

Reciprocal;
Nonreciprocal.
 Reciprocal Translocations
This type of rearrangement results from –
Breakage or recombination involving nonhomologous
chromosomes, with reciprocal exchange of the broken-off
or recombined segments.

Usually only two chromosomes

are involved, and because the
exchange is reciprocal,
the total chromosome number
is unchanged.
Reciprocal Translocations
Such translocations are usually without phenotypic effect;
However, they are associated with a high risk for
unbalanced gametes and abnormal progeny.

They come to attention either during prenatal diagnosis or

when the parents of a clinically abnormal child with an
unbalanced translocation are karyotyped.
Balanced translocations are more commonly found in
couples who have had two or more spontaneous
abortions and in infertile males than in the general
population.
 Reciprocal Translocations

The existence of translocations presents challenges for the

process of chromosome pairing and homologous
recombination during meiosis;
When the chromosomes of a carrier of a balanced
reciprocal translocation pair at meiosis-
They must form a quadrivalent to ensure proper
alignment of homologous sequences (rather than the
typical bivalents seen with normal chromosomes).
 Reciprocal Translocations
In typical segregation, two of the four chromosomes in the
quadrivalent go to each pole at anaphase;
However, the chromosomes can segregate from this
configuration in several ways, depending on which
chromosomes go to which pole.
Alternate segregation, the usual type of meiotic
segregation;
Produces balanced gametes that have either a normal
chromosome complement or contain the two reciprocal
chromosomes.
Other segregation patterns, however, always yield
unbalanced gametes.
Balanced translocation
 Robertsonian Translocations
The most common type;
Involve two acrocentric chromosomes that fuse near
the centromere region with loss of the short arms.
Nonreciprocal;
Karyotype has only 45 chromosomes;

Including the
translocation
chromosome, which is
made up of the long
arms of two acrocentric
chromosomes.
 Robertsonian Translocations
The short arms of all five pairs of acrocentric
chromosomes consist:
1. Largely of various classes of satellite DNA;
2. Hundreds of copies of ribosomal RNA genes;
Loss of the short arms of two acrocentric chromosomes
is not deleterious;
The karyotype is considered to be balanced, despite
having only 45 chromosomes.

Robertsonian translocations are typically, although not

always, pseudodicentric , reflecting the location of the
breakpoint on each acrocentric chromosome.
 Robertsonian Translocations
Can involve all combinations of the acrocentric
chromosomes;
rob(13;14)(q10;q10) and rob(14;21) (q10;q10) —are
relatively common.
The translocation involving 13q and 14q is found in
approximately 1 person in 1300 ;

Rare individuals with two copies of the same type of

Robertsonian translocation have been described;
These phenotypically normal individuals have only 44
chromosomes and lack any normal copies of the
involved acrocentrics, replaced by two copies of the
 Robertsonian Translocations
Although a carrier of a Robertsonian translocation is
phenotypically normal, there is a risk for unbalanced
gametes ;
Unbalanced offspring.
The risk for unbalanced offspring varies according to the particular
Robertsonian translocation and the sex of the carrier parent;
Carrier females in general have a higher risk for
transmitting the translocation to an affected child.
Chromosome 21 - are at risk for producing a child with
translocation Down syndrome.
 Insertions
Type of nonreciprocal translocation;
A segment removed from one chromosome is inserted
into a different chromosome:
1. either in its usual orientation with respect to the
centromere
2. or inverted.

They require three chromosome breaks, insertions are

relatively rare.
Insertions
Abnormal segregation in an insertion carrier can
produce :
1. Offspring with duplication or deletion of the
inserted segment;
2. Normal offspring;
3. Balanced carriers.
 The average risk for producing an abnormal child can
be up to 50%,;
Prenatal diagnosis is therefore indicated.
 Inversions
A single chromosome undergoes two breaks and is
reconstituted with the segment between the breaks
inverted.
Inversions are of two types:
1. Paracentric, in which both breaks occur in one arm
(beside the centromere);
2. Pericentric, in which there is a break in each arm
(around the centromere).

Pericentric inversions can be easier to identify

cytogenetically when they change the proportion of the
chromosome arms as well as the banding pattern.
 Inversions

An inversion does not usually cause an abnormal phenotype

in carriers because it is a balanced rearrangement.
Its medical significance is for the progeny;
 A carrier of either type of inversion is at risk for producing
abnormal gametes;
unbalanced offspring ;
 Inversions
When an inversion is present, a loop needs to form to
allow alignment and pairing of homologous
segments of the normal and inverted chromosomes
in meiosis I
When recombination occurs within the loop, it can
lead to the production of unbalanced gametes:
1. gametes with balanced chromosome complements
(either normal or possessing the inversion) ;
2. gametes with unbalanced complements are formed ;

 depending on the location of recombination events.

 Inversions
When the inversion is paracentric:
The unbalanced recombinant chromosomes are acentric or
dicentric and typically do not lead to viable offspring ;
 The risk that a carrier of a paracentric inversion will have a
liveborn child with an abnormal karyotype is very low
indeed.
 Inversions
A pericentric inversion - unbalanced gametes with :
Both duplication and deficiency of chromosome
segments.
The duplicated and deficient segments are the segments that
are distal to the inversion.
 Inversions
Overall, the risk for a carrier of a pericentric inversion
leading to a child with an unbalanced karyotype is
estimated to be 5% to 10%.

 Each pericentric inversion, however, is associated

with a particular risk, typically reflecting the size
and content of the duplicated and deficient segments.
Mosaicism for Chromosome Abnormalities
Two or more different chromosome complements are
present in an individual
Called mosaicism.
Typically detected by convenional karyotyping;
Interphase FISH analysis or chromosomal microarrays.

A common cause of mosaicism is nondisjunction in an

early postzygotic mitotic division.
For example, a zygote with an additional chromosome 21
might lose the extra chromosome in a mitotic division
and continue to develop as a 46/47,+21 mosaic.
Down syndrome; Turner syndrome.
Mosaicism for Chromosome Abnormalities
Detected in lymphocytes, in cultured cell lines or in
prenatal samples- difficult to assess the significance of
mosaicism;
Especially if it is identified prenatally.
The proportions of the different chromosome complements seen
in the tissue being analyzed may not necessarily reflect the
proportions present in other tissues or in the embryo during its
early developmental stages.
Mosaicism can also arise in cells in culture after they were
taken from the individual;
True mosaicism- individual;
Pseudomosaicism- occurred in the laboratory.
 Incidence of Chromosome Anomalies
The major numerical disorders of chromosomes observed in
liveborns are:
 Three autosomal trisomies:
Trisomy 21, Trisomy 18, Trisomy 13
 Four types of sex chromosomal aneuploidy:
Turner syndrome (45,X), Klinefelter syndrome (47,XXY,)
47,XYY , 47,XXX

 Triploidy and tetraploidy account for only a small

percentage of cases, typically in spontaneous abortions.
 CHROMOSOME AND GENOME ANALYSIS IN
CANCER

Mutations also occur in somatic cells throughout life and are

a hallmark of cancers:
1. Hematological neoplasias (leukemias/lymphomas)
2. Solid tumor progression.

The chromosome and genomic changes seen in cancer cells

are numerous and diverse.
 The association of cytogenetic and genome analysis with
tumor type and with the effectiveness of therapy is already
an important part of the management of patients with
cancer.
Thank you for attention!
Lecturer:
Salome Abechkhrishvili
SEU