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Mechanisms of origin of numerical and structural basis of ch

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Christian Scerri

on 28 February 2018

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Transcript of Mechanisms of origin of numerical and structural basis of ch

Mechanisms of unbalanced rearrangements - Deletions

Chromosomal breakage and loss of fragments


Require a single break and capping of the broken end with a telomere

Cri du chat - terminal deletion of 5p

Moon face


Characteristic cry
Numerical and structural basis of chromosome abnormalities - Mechanisms
Chromosomal abnormalities

not generally due to mutations in single genes,
the result of structural alterations that can be seen under the light microscope.
include the rearrangement of genetic material in a chromosome, or numerical abnormalities due to the gain or loss of a chromosome.

Polyploidy - abnormal # of chromosome sets
Aneuploidy - abnormal chromosome number


Deletion syndromes
Ring chromosomes
Centromeric fusions (Robertsonian translocations)
Reciprocal translocations
Polyploidy - Triploidy (3 sets)

Has been reported in humans
can survive to birth but die shortly after
: = 2:1
2-3% of normal pregnancies
Triploidy (contd)

The result of either
digyny (dī-jin′ē-ă)
extra haploid set from mother - normal sperm, diploid oocyte
predominates in late pregnancy miscarriages and birth
characterised by marked asymmetric intrauterine growth restriction, marked adrenal hypoplasia, and a very small, placenta

diandry (dī-an′drē-ă)
extra haploid set from father - diploid sperm, haploid oocyte - or haploid oocyte, fertilised by two sperms (dispermy).
characterised by a normally sized or mildly symmetrically growth retarded fetus with normal adrenal glands, and an abnormally large, cystic placenta

Both can show a wide variety of congenital anomalies such as
complete syndactyly (webbing/fusion) of the third and fourth fingers and of the toes,
abnormal genitals,
cardiac, urinary tract, and brain anomalies
Polyploidy - Tetraploidy (4 sets)

Rarely present in a live birth

Could be due to
double haploid, sperm fertilisation with a diploid oocyte or
two haploid oocytes, each fertilised with one haploid sperm that fuse into one cell.
Aneuplody (an-yu̇-ˌploide)

Number of chromosomes is not an exact multiple of the monoploid number (humans = 23)

Caused by extra or missing chromosome

Present in around 4% of live births.

Incidence of autosomal aneuploidies is directly related to increasing maternal age.

Usually due to non-disjunction event during meiosis I or meiosis II

Non-disjunction - failure of homologous chromosomes to separate properly
1. Lack of tension, activates Mad2.
2. Activated Mad2 together with BubR1 and Cdc20 forms a complex with APC, inhibiting the laters ubiquitating function.
3. Securin is not ubiquinated and thus stabilised.
4. Securin binds tightly to separin.
5. Anaphase is arrested.
Aneuploidy (Contd)

Estimated aneuploidy in sperm is 4.5%
Smoking, alcohol and caffeine have all been implicated

Aneuploidy rates in human oocytes can reach 60% or higher

Aneuploidy rates are correlated with maternal age.
If nondysjunction occurs at M1, gamete gets both a maternal and paternal chromosome

If at M2, the gamete has 2 maternal or 2 paternal chromosomes
Common aneuploidies - Trisomy 21

95% of Downs syndrome patients
Characteristic phenotype risk increases with maternal age (especially after 30)
Usually occurs as nondisjunction at Meiosis 1
1/800 births
Trisomy 21 - Signs and Symptoms

Growth failure
Mental retardation
Flat occiput
Dysplastic ears
Intestinal stenosis
Hypotonic muscles
Webbed toes, widely paced
Broad flat face
Slanting eyes
Short nose
Small and arched palate
Big tongue
Short, broad hands
Congenital heart disease
Trisomy 18

Mental retardation
failure to thrive
microcephaly, microphthalmia,
malformed ears,
severe malformations of the heart
rocker bottom feet (congenital vertical talus)
characteristic hand position
Rarely survive to birth (1/7500 births)

Trisomy 13

severe mental retardation,
growth retardation, severe
polydactyly - extra fingers or toes
cleft lip and palate,
most die within first days or weeks - few live past their first year
1/20,000 births
X chromosome

Aneuploidy for the X chromosome is among the most common of cytogenetic abnormalities
Tolerated because of X chromosome inactivation - occurs early in embryogenesis
Occurs randomly between maternal vs paternal - some genes escape inactivation.
Once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism.
Inactive X is functionally inactive (therefore females are mosaics)
Presence of Y chromosome determines male gender
Klinefelter Syndrome XXY

Sexually underdeveloped
Rudimentary testes and prostate glands
Long arms and large hands
May develop breast tissue
May be slow learners
1 Barr body - (1 inactivated X chromosome)
Most of symptoms due to extra gene copies that are not inactivated (mainly in the pseudautosomal region)
1/500 male births
Triple - X female XXX

Tallness and menstrual irregularities
Less intelligent than siblings on average
Usually fertile and at risk of having
children with extra X
2 Barr bodies
1/1000 female births
Turner Syndrome XO

Sexually underdeveloped
Wide spaced nipples
Skin flaps on back of neck
Normal intelligence
1/2000 live female births
Only anuploid condition that seems unrelated to the age of the mother
Jacobs syndrome XYY

Normal phenotype
increased height
slight speech and reading problems
Structural Chromosomal Abnormalities

1/375 newborns


A structural chromosomal abnormality with a gain or loss of the normal complement of genetic material


Normal complement of genetic material is maintained

Usually no clinical significance for the patient, but may have consequence for offspring
Ring Chromosomes

Formed from two terminal deletions -a break in both arms, with fusion of the ends

Represent a form of terminal deletion

Added feature of being mitotically unstable

Have been found in nearly all human chromosomes

More likely to be caused by the deletion of genes in the telomeric regions

Three types of ring chromosome are relatively common:
large rings with minimal loss from the terminal segments

very small rings as extra chromosomes

formed from the X-chromosome, generally found in females with features of Turner syndrome.
Interstitial deletions

require two breaks with loss of the interstitial segment

partial monosomies can produce severe abnormalities and death of the embryo

only embryos with small deletions are likely to survive.

Extensive studies on
two distinct and clinically very different syndromes:
Angelman syndrome
Prader–Willi Syndrome
intense hyperphagia,
poor muscle tone,
hypoplastic genitalia and
moderate intellectual impairment

Angelman syndrome
severe intellectual impairment,
delayed or absent speech,
spontaneous outbursts of laughter
characteristic facial features.

Both due to the same deletion
Difference due to genetic imprinting
SNRPN is a gene that is imprinted by the mother,
UBE3A - closely linked - is imprinted by the father.
Paternal chromosome - PWS
Maternal chromosome - AS

Unbalanced rearrangements that result in partial trisomy.
Milder than deletions but with similar clinical features
Unequal crossing over - so one chromosome has a duplication, the other an interstitial deletion
Duplications can be
- retain the same order of gene loci or
inverted -
complete reversal of loci
Ring Chromosome

Chromosomes with terminal deletions on both ends (thus lacking identifiable
telomeric sequences) are likely to form ring chromosomes

Quite rare but have been detected for every human chromosome.

When the centromere is within the ring, a ring chromosome is expected to be mitotically stable.
Sometimes the two sister chromatids become tangled in their attempt to disjoin at anaphase.

Result in breakage followed by fusion - forming larger and smaller rings.

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) and three copies of the genetic material of the other arm (partial trisomy).

The most common isochromosome - isochromosome of the long arm of the X chromosome, i(Xq) (Turner syndrome)

Others include isochromosomes for the short arm of chromosome 18, i(18p), and for the short arm of chromosome 12, i(12p).

Commonly seen in malignant solid and haematological tumours
Balanced Rearrangements

Chromosomal rearrangements called balanced when all chromosomal material is present even though it is packaged differently.

Though no phenotypical effect in the person, can pose a threat to the subsequent generations - likely to produce a high frequency of unbalanced gametes

The risk can range from 1% to as high as 20%.
Balanced Rearrangements - Inversions

Occurs when a single chromosome undergoes two breaks and is reconstituted with the segment between the breaks inverted.

Two types
- not including the centromere -
both breaks occur in one arm
does not change arm ratio
can only be identified by banding or FISH
gametes are either normal, inverted like parent or else non viable

- including the centromere -
a break in each arm
changes arm ratio - easier to identify
can give rise to similar gametes like parent or else to unbalanced gametes
higher chance of abnormalities in offsprings - estimated to be 5 to 10%

Involves the exchange of chromosome segments between two, usually nonhomologous,

Two main types:
Reciprocal and

Reciprocal Translocations

Results from breakage of nonhomologous chromosomes followed by reciprocal exchange of the broken-off segments.

Usually only two (rarely more) chromosomes are involved

As exchange is reciprocal, the total chromosome
number is unchanged

Relatively common - 1 in 600 newborns.

Such translocations are usually harmless, but can give rise to unbalanced gametes
Robertsonian Translocation

Combines the long arms of two acrocentric chromosomes: the tiny short arms are lost, and the result is a reduced number of chromosomes

The karyotype 'loses' two acrocentric chromosomes and 'gains' a single metacentric chromosome.

The human genome includes five acrocentric chromosomes: 13, 14, 15, 21, 22

Two (13q14q and 14q21q) are relatively common.

13q14q - 1 person in 1300 - the single most common chromosome rearrangement in humans

14q21q particularly important as unbalanced gametes can give rise to Down's syndrome

The risk of unbalanced offspring varies according to the particular Robertsonian translocation and the sex of the carrier parent; carrier females in general have a higher risk of transmitting the translocation to an affected child.
Monosomy 14, trisomy 14 and monosomy 21 are lethal
Observed figures for Robertsonian translocation carriers bearing an offspriong Down syndrome
10% if the mother is the translocation carrier
2.5% if the father is the translocation carrier.
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