Chromosomal abnormalities

Lecture Summary
• Chromosome rearrangements associated
with:
– abnormal phenotype (unbalanced)
– reproductive consequences
• Abnormalities identified by
– metaphase chromosome analysis
– molecular cytogenetic techniques
Chromosome abnormalities in
humans
• Spermatozoa 10%
• Mature oocytes 25%
• Spontaneous miscarriage 50%
• Live births 0.5-1%
• Most due to maternal meiotic non
disjunction
• Strongly related to maternal age
 When to suspect it

• Unexplained infertility/ balanced

translocation
• Multiple abortion >2
• Prior case of defective baby
 Incidence
• The earlier the abortion the more likely to
be chromosomal
• 50% of spontanous abortion are
chromosomal abnormal
• Mostly triploidy, 45 XO, trisomy 16
• 98% of fetus with turner abort
• Generally 6/1000 the incidence of
chromosomal abnormalities
Chromosome abnormalities in
miscarriages
Incidence %
Trisomy 13 2
Trisomy 16 15
Trisomy 18 3
Trisomy 21 5
Other Trisomy 25

Monosomy X 20
Triploidy 15
Tetraploidy 5
Other 10
 Chromosome abnormalities
• Triploidy → rare at birth – lethal

• Trisomy 16 → Most common in spontaneous miscarriages

→ Completely lethal. Cause unknown

→ 95% miscarry
• Trisomy 13 &18

→ 80% miscarry
• Trisomy 21

→ 50% miscarry
• Klinefelters
→ 1% at conception
• 45X → 98% miscarry, probably mosaic survive
 When to suspect it…continue
• Presence of congenital anomalies
– 45% have minor single anomalies
– 9% 3 minor anomalies
– 1.5% HAVE major anomaly
• 2 or more major anomalies may represent
genetic syndrome or chromosomal
abnormalities(10%).
 Variations in Chromosomal
Number
• Euploidy – the normal number and sets of
chromosomes

• Polyploidy – the presence of three or more

complete sets of chromosomes

• Aneuploidy – the presence of additional or

missing individual chromosomes
 Forms of Chromosomal Non-Disjunction

Euploidy
Triploidy complete extra set of chromosomes - 69
caused by fertilization of an egg by more than one
sperm or an egg that failed to divide

Tetraploidy complete extra diploid set of chromosome - 92

caused by a failure of the first zygotic division

Aneuploidy gain or loss of a single chromosome

failure in meioses (usually)

Monosomies loss of a chromosome – Turner syndrome

autosomal monosomies are lethal
sex monosomies survive

Trisomies gain of a chromosome

- Down / Tri 13 / Tri 18 / Klinefelter
 Types of Polyploidy
• Triploidy – three sets of chromosomes
23 x 3 = 69

• Tetraploidy – four sets of chromosomes

23 x 4 = 92
How does polyploidy arise?

Triploidy - 69XXX, 69XXY, 69XYY

- most result from dispermy
- can have a haploid sperm fertilize a diploid egg
- about 1% of all conceptions are triploid
- 99% die before birth
- triploidy seen in about 1 in 10,000 live births
- most die within one month

Teraploidy
- observed in 5% of spontaneous abortions
- often due to failure of cytokinesis
- lethal
Summary - Polyploidy

- does not involve mutation of any gene per se

- it is the duplication of the entire set of chromosomes
- defect is a change in the number of copies of genes
present in the genome

Mechanisms
- meiosis/cytokinesis mismatch
- mitosis/cytokinesis mismatch
- dispermy

- in humans – it is lethal.
 Aneuploidy in Humans
• When aneuploidy occurs in humans,
syndromes can result. Examples include
the following:
1. Trisomy 13
2. Trisomy 18
3. Down Syndrome
3. Turner Syndrome
4. Klinefelter Syndrome
5. XYY Syndrome
 Aneuploidy caused by
• Non-disjunction
– failure of homologous chromosomes to separate in
anaphase I
– failure of sister chromatids to separate at meiosis II
• Anaphase lag
– Chromosomal loss via micronucleus formation
caused by delayed movement of
chromosome/chromatid during anaphase
• results in daughter cell deficient of that chromosome or
chromatid
 Changes in Chromosome Number
• Nondisjunction occurs during meiosis I
when the members of a homologous pair
both go into the same daughter cell or
during meiosis II when the sister chromatids
fail to separate and both daughter
chromosomes go into the same gamete.
• The result is a trisomy or a monosomy.
• As a consequence of nondisjunction, some
gametes receive two of the same type of
chromosome (disomy) and another gamete
receives no copy (nullisomy).
• Offspring results from fertilization of a normal
gamete with one after nondisjunction will have
an abnormal chromosome number or
aneuploidy.
– Trisomic cells have three copies of a particular
chromosome type
– Monosomic cells have only one copy of a particular
chromosome type and have 2n - 1 chromosomes.
• If the organism survives, aneuploidy typically
leads to a distinct phenotype.
 Aneuploidy

Autosomal monosomy is rarely observed in

spontaneously aborted fetuses or in live births.

Most autosomal trisomies are also lethal

Nondisjunction in meiosis I
Nondisjunction in meiosis II
 Aneuploidy

• As women age
– some chromosomes exhibit non-disjunction in oocytes

• 13, 18, 21 associated with age

• 16 and X only first meiotic division associated with age
• Most chromosome abnormalities incompatible with life
• Will miscarry
Changes in Chromosome Structure
• A mutation is a permanent genetic change.
• A change in chromosome structure is a
chromosome mutation.
• Radiation, organic chemicals, or even
viruses may cause chromosomes to break,
leading to mutations.
• Chromosomal mutations include inversion,
translocation, deletion, and duplication.
Deletions - loss of a chromosomal segment

Duplication - an extra copy of a chromosomal segment

Translocations - a chromosomal segment has been

transferred from one chromosome to another.

Two types Reciprocal translocations

Robertsonian translocation

Inversions - order of a chromosome segment has been

reversed
Single Chromosome Disorders
1.Deletion
• Genetic
material is
missing

2. Duplication
• Genetic
material is
present twice

3. Inversion
• Genetic
material is
“flipped”
 Two Chromosome Disorders
(Both types are called “translocation”)

Insertion (unreciprocal
translocation)
• Genetic material is added from
another chromosome

Reciprocal Translocation
• Material is swapped with another
chromosome
• Breakage of a chromosome can lead to four types of changes in
chromosome structure.
• A deletion occurs when a chromosome fragment lacking a
centromere is lost during cell division.
– This chromosome will be missing certain genes.
• A duplication occurs when a fragment becomes attached as an
extra segment to a sister chromatid.
• An inversion occurs when a chromosomal
fragment reattaches to the original chromosome
but in the reverse orientation.
• In translocation, a chromosomal fragment joins
a nonhomologous chromosome.
– Some translocations are reciprocal, others are not.
 Deletions
• Deletions occur when a single break
causes a lost end piece, or two breaks
result in a loss in the interior.
• An individual who inherits a normal
chromosome from one parent and a
chromosome with a deletion from the
other parent no longer has a pair of alleles
for each trait, and a syndrome can result.
Deletion - deficiency
 Deletions
• Terminal • Interstitial
• Cri du chat, 5p15 • Williams, 7q11.2,
• Wolf-Hirschhorn, – microdeletion (FISH)
4p36 • Retinoblastoma, 13q14
• Prader-Willi, 15q11.2
• Angelman, 15q11.2
• DiGeorge, 22q11.2
 Deletions

• Deletions are rare, as are monosomies

• Can be de novo or inherited

– due to translocation or inversion in parent

• Would not reproduce

• Duplication results in a chromosome
segment being repeated in the same
chromosome or in a homologous
chromosome, producing extra alleles for a
trait.
• An inverted duplication in chromosome 15
causes inv dup 15 syndrome with poor
muscle tone, mental retardation, and
related symptoms.
 Translocations

Translocation is a exchange of chromosomal segments

between two, nonhomologous chromosome.

Two major types

Reciprocal translocation - two non-homologous

chromosomes exchange information

Robertsonian translocation - two non-homologous

acrocentric chromosomes break at the centromere and
long arms fuse. The short arms are often lost.
 Translocation
• Translocation: a fragment of a
chromosome is moved ("trans-located")
from one chromosome to another - joins a
non-homologous chromosome.
• The balance of genes is still normal (nothing
has been gained or lost) but can alter
phenotype as it places genes in a new
environment.
• Can also cause difficulties in egg or sperm
development and normal development of a
zygote.
 Chromosome Abnormalities:
Structural
• Chromosome breakage with subsequent
reunion in a different configuration

Reciprocal translocation
Chromosome Translocations
– Balanced Reciprocal Translocations
• no loss or gain of genetic information
• position change
• no phenotype consequences (position effect, gene
disruption)
• reproductive consequences
 Reciprocal Translocation

- two non-homologous chromosomes exchange

information

- if no genes are broken, individuals appears normal

(no phenotype)
- no gain or loss of genetic information
- individuals are translocation carriers

- if one of the breaks occurs in a gene

- gene can be disrupted
- can have a phenotype
 translocation carriers

- have high risk of producing unbalanced gametes during

meiosis because of chromosomal pairings problems
-nondysjunction

- unbalanced gametes produce abnormaloffspring,

embryonic deaths

- What might you suspect in a family observed to have

offspring with multiple birth defects and many
spontaneous abortion?

- may be a translocation carrier

Reciprocal Translocations
 Reciprocal translocation
• 2:2 segregation
– Two chromosomes per gamete
– Could produce normal, balanced or unbalanced
gametes

• 3:1 segregation
– Three chromosomes to 1 gamete
– One chromosome to other gamete
– All will be unbalanced
 Reciprocal
translocation
2:2 segregation
• Pachytene quadrivalent

• Alternate
gives normal or balanced
gametes
 Reciprocal
translocation
2:2 segregation
• Adjacent 1 gives unbalanced

• Adjacent 2 gives unbalanced

 Reciprocal translocation
3:1 segregation
• Pachytene quadrivalent

• A, C, D together – trisomy for material on C

• B alone – monsomy for material on B
"Philadelphia chromosome"
Translocation 9:22
• Translocation

Figure 8.23Bx
Spectral Karyotype (SKY) of a breast cancer
cell

Paul Edwards (Cambridge)

 Reciprocal Translocations: Points
to consider
• Look at the karyotype following this slide:
– What is the modal chromosome number?
– Is there a rearrangement present?
– How many derivative chromosomes do you
see?
– Is this a balanced karyotype and if so, why?
Reciprocal Translocation

46,XX,t(2;17)(q21.3;q25.2)
 Balanced Reciprocal
Translocation: A closer look

normal 17
der (2)
der (17)

normal 2
*der = derivative chromosome that is structurally rearranged, involving
2 or more chromosomes
 Reciprocal Translocations: Points
to consider
• Referring to the previous slide:
– What is the modal chromosome number? 46
– Is there a rearrangement present? Yes, a reciprocal
translocation.
– How many derivative chromosomes do you see? Two.
– Is this a balanced karyotype and if so, why? There is
no apparent cytogenetic loss or gain of chromosome
material, just a repositioning effect.
 Robertsonian Translocation
• Joining of the long arm of two acrocentric
chromosomes to form a single derivative
chromosome
• loss of p arm material without phenotype
effect
• modal chromosome number 45 in
balanced carriers
Robertsonian Translocations
Robertsonian Translocation
Fusion of two acrocentric chromosome occurs (A)
to form a single derivative chromosome (B).

n = 46 n = 45
With a balanced Robertsonian translocation, the modal
number is reduced from 46 to 45 chromosomes.
 Robertsonian Translocation

- occurs most frequently with acrocentric chromosomes

(13,14,15,21,22).

- produce one new large chromosome made from the

two long arms of two different chromosomes.

- two short arms of each chromosome are lost

Example - Down’s syndrome

Robertsonian Translocation: Points
to consider
• Look at the karyotype following this slide:
– What is the modal chromosome number?
– Is there a rearrangement present?
– How many derivative chromosomes do you see?
– Is this a balanced karyotype and if so, why?
– What material has been lost with this rearrangement,
if any?
Robertsonian Translocation

45,XX,der(13q;14q)
Robertsonian translocation of
chromosomes 13 and 14
 Robertsonian Translocation:
Points to consider (1)
• Referring to the previous slide:
– What is the modal chromosome number? 45
– Is there a rearrangement present? Yes, two acrocentric
chromosomes have joined at or near the centromere.
– How many derivative chromosomes do you see? One,
the acrocentric long arms have joined to form a single
derivative chromosome.
– Is this a balanced karyotype and if so, why? Yes, There
is no loss of clinically relevant euchromatin with the
formation of a single derivative chromosome.
Robertsonian Translocation: Points
to consider (2)
• What material has been lost with this
rearrangement, if any? The acrocentric p
arms of chromosomes 13 and 14 have
been lost with this rearrangement. Since
the p arms contain ribosomal genes that
are found on the short arms of other
acrocentric chromosomes, there is no
phenotype effect.
 Robertsonian Translocations

Other chromosomal forms of

Down syndrome - ?inheritance

Can result in Down syndrome

Segregation of
chromosomes at
meoisis in a 14-
21 translocation
carrier
Robertsonian translocation
 21:21 fusion
• At meiosis cannot form normal gametes
– Either disomy or nullisomy

• Never give normal offspring

– Trisomy 21 Down
– Monosomy 21 lethal - miscarry

• 6 families described
– 21 Down children
– 12 miscarriages
– 4 families female carrier, and 2 were male carrier
 Common form of structural rearrangements

Robertsonian Translocation vs. Reciprocal Translocation

 Reciprocal vs Robertsonian:
• Reciprocal -> 2 derivative chromosomes,
46 chromosomes total

• Robertsonian -> 1 derivative chromosome

• 45 = balanced
• 46 = unbalanced

Either may or may not be inherited*

 Inversion
• Inversion involves a segment of a
chromosome being turned 180 degrees;
the reverse sequence of alleles can alter
gene activity.
• Crossing-over between inverted and
normal chromosomes can cause
recombinant chromosomes due to the
inverted chromosome needing to form a
loop to align.
Inversion
Inversion of Chromosome 16
 Structural Aberrations
Balanced rearrangements No visible loss or gain of genetic material:

Inversions ( peri- and paracentric)

a piece of chromosome flipped around and reinserted

if it includes the centromere - pericentric
if it excludes the centromere - paracentric

These have slightly different genetic consequences as a result

of meiotic pairing

Can result in abnormal pregnancies and SAB

May or may not be inherited*

 Inversions
http://www.tokyo-med.ac.jp/genet/cai-e.htm

Pericentri Paracentric
inversion Inversion
 Other forms
of
chromosome abnormalities

• deletions
• duplications
• insertions
• rings
• isochromosomes

WHY?? part of being human

Deletions
 Ring chromosomes
• Often unstable in mitosis

• Often only find ring in proportion of cells

• Other cells usually monosomic as lack ring

Ring chromosomes

Ring X chromome.
Isochromosomes

Isochromosome
Fragile X
 8.23 Connection: Alterations of
chromosome structure can
cause miscarriage, birth
defects and cancer
• Chromosome breakage can lead to
rearrangements that can produce genetic
disorders or cancer
– Four types of rearrangement are deletion,
duplication, inversion, and translocation
 Consequences Of Balanced
Structural Rearrangements
• Balanced carriers
• phenotypic risks - low
• reproductive risks - > background
• increased risk of miscarriage
• increased risk of offspring with
– mental retardation
– congenital anomalies

• WHY?
 Chromosome Abnormalities:
Structural
• Unbalanced Rearrangements
– loss or gain or chromosome material
– many different types
• Isochromosomes
• Deletions
• Duplications
– abnormal phenotype association
 Chromosomal shorthand
Abbreviation What it means
46, XY Normal male
46, XX Normal female
45, X Turner syndrome female
47, XXY Klinefelter syndrome male
47, XYY Jacobs syndrome male
46, XY del (7q) Male missing part of long arm of chromosome
7
47, XX+21 Female with trisomy 21
46, XY t (7;9) Male with translocation between short arm of
(p21.1;q34.1) chromosome 7 band 21.1 and long arm of
chromosome 9 band 34.1
Karyotype nomenclature
Table 1. Karyotype Nomenclature

Karyotype Description
46,XY Normal male
47, XX,+21 Female with trisomy 21, Down Syndrome.
47, XY,+21 / 46, XY Male mosaic for trisomy 21 and normal cells
46, XY, del(4)(p14) Male with distal deletion of the short arm of
chromosome 4 band designated 14.
46,XX, dup (5p) Female with a duplication of short arm of
chromosome 5.
45, XY, -13, -14, t(13q;14q) Male with a b alanced Robertsonian translocation
of chromosome 13 and 14, with a no rmal 13 and
normal 14 missing.
46, XX, t(11;22)(q23;q22) Male with a balanced reciprocal translocation
46,XX, inv(3)(p21;q13) Female with an i nversion on chromosome 3 from
p21 to q13; because it includes the centromere this
is a pericentric inversion.
46, X.r(X) A female with one normal X and one ring X
chromosome.
46, X, i(Xq) Female with one normal X chromosome and and
isochromsome of the long arm of the X.
 Summary: Why do we study
human chromosomes?
• Chromosome disorders - major category
of genetic disease
– Responsible for >100 identifiable syndromes
– More common than all mendelian single gene
disorders!
– 1% livebirths
– 2% pregnancies
 Clinical Indications for
Chromosome Analysis
• Problems of early growth and
development
• Stillbirth/neonatal death
• Fertility problems
• Family history of chromosome
rearrangement
• Pregnancy indications – LMA, U/S abn etc
• Neoplasia
Fate of human implanted embryos
 Case 3
• Clinical referral:
– complex cyanotic congenital heart defect
requiring multiple surgeries
– borderline mental retardation
– short stature
– Turner syndrome?
46,XX,?del(22)(q11.2q11.2)
 Microdeletion Identification:
Locus Specific Probes
• Unique sequences
localized within a
chromosome band
– microdeletion screen
– microduplication screen
– identification of
chromosome region
• structural rearrangements
• deletions, duplications
Locus Specific Probe: 22q11.2

46,XX,?del(22)(q11.2q11.2).
 Microdeletion 22q11.2
• Velocardiofacial Clinical Spectrum
– cleft palate
– cardiac - VSD, Tetralogy of Fallot
– typical facies: prominent nose, narrow palpebral
fissures, slightly retruded mandible
– learning disabilities
– slender hands and digits
– minor auricular anomalies
– overlap with DiGeorge syndrome
– http://www.around.ntl.sympatico.ca/~a815/chr22.ht
m
 Genetic Follow-up:
• Genetic counseling
• Parental chromosome studies
• Extended family studies for inherited
chromosome rearrangement
• Prenatal diagnosis options for future
pregnancies
Sex Determination

46,XY
female

SRY on Xp - XX male