S402F-Lecture 9 2023 - OLE

BIOL-S402F Medical Genetics and Immunology
(Part B: Medical Genetics)

Lecture 9
By Dr. Andy YY CHEUNG

cheungyy@hkmu.edu.hk
In human cells, which organelles contain DNA
materials?
Mitochondrial DNA
Course outline:
4. Molecular Basis of Genetic Diseases
a. Gregor Mendel and the Laws of Inheritance Lectures 7
b. DNA as the Basis of Inheritance
c. Common monogenic genetic diseases Lectures 8
d. Complex diseases
5. Genetics in Diseases and Development

a. Cytogenetics Lectures 9
b. Common chromosomal abnormalities
c. Epigenetics Lectures 10
d. Mitochondrial DNA inheritance
e. Development and sex determination Lectures 11
f. Clinical genetics and ethical issues
6. Cancer Genetics
a. Genetic factors and environmental factors in cancers
b. Mutations in cell cycle regulatory genes Lectures 12
c. Mutations in the DNA repair system
d. Epigenetics in cancer
Mitosis (cell cycle and cell division)
Stages of mitosis
prepares for
mitosis (G2)
the cell grows (G1)
replicates its DNA (S)

Prophase
• The first and longest phase of

mitosis is prophase
• Each chromosome is made of two
genetically identical chromatids,
joined by a centromere
• During DNA replication, genetic
material is loosely packed as
chromatin
• However, during mitosis DNA needs
to be more tightly packed to allow
for easier separation in anaphase
• To help with this, at the start of
prophase, chromatin begins
condensing into chromosomes
https://commons.wikimedia.org/wiki/File:Prophase.svg
Prophase
Condensation of chromosomes
• DNA that was replicated in
interphase is condensed from DNA
strands with lengths reaching 0.7
μm down to 0.2-0.3 μm
• This process employs the
condensin complex
• Condensed chromosomes consist
of two sister chromatids joined at
the centromere
Prophase
Movement of centrosomes
• During prophase in human cells,
centrosomes move far enough
apart to be resolved using a light
microscope
• Microtubule activity in each
centrosome is increased due to
recruitment of γ-tubulin
• Replicated centrosomes from
interphase move apart towards
opposite poles of the cell,
powered by centrosome
associated motor proteins
Prophase
Formation of the mitotic spindle

• The movement of centrosomes to
opposite poles is accompanied in
human cells by the organization of
individual radial microtubule arrays
by each centromere
• Interpolar microtubules from both
centrosomes interact, joining the
sets of microtubules and forming the
basic structure of the mitotic spindle
• The mitotic spindle is of great
importance in the process of mitosis
and will eventually segregate the
sister chromatids in metaphase
Prophase
Beginning of nucleoli breakdown

• The nucleoli begin to break down
in prophase, resulting in the
discontinuation of ribosome
production.
• This indicates a redirection of
cellular energy from general
cellular metabolism to cellular
division
• The nuclear envelope stays intact
during this process
Prometaphase
• In this stage, the chromosomes

finish condensing into their
compact state
• The nuclear envelope begins to
break down, allowing spindle fibres
to attach to the chromosomes at a
site called the kinetochore (an area
of the centromere found on each
sister chromatid)
• The sister chromatids are attached
to spindles that originate from the
opposite centrosome, linking the
two together
https://commons.wikimedia.org/wiki/File:Prometaphase.svg
Metaphase
• At this stage, the chromosomes

align upon a theoretical line
known as the metaphase plate
• The centrosomes have finished
moving and are located at
opposite ends of the cell
https://en.wikipedia.org/wiki/Metaphase
Metaphase
• At this stage, the cell will check

that all the chromosomes are
aligned along the metaphase plate,
with their kinetochores correctly
attached
• This helps to ensure sister
chromatids are split evenly
between the two daughter cells
• An error in chromosomal
alignment or spindle attachment
will result in the cell halting further
progress until the problem is fixed
https://en.wikipedia.org/wiki/Metaphase
Anaphase
• During this stage, sister chromatids

are pulled to opposite ends of the
cell
• The spindle fibres contract,
breaking the chromatids at the
centromere and moving them to
opposite poles of the cell
• Spindle fibres not attached to
chromatids will elongate the cell to
prepare it for division
https://en.wikipedia.org/wiki/Anaphase
Telophase
• In this phase, the cell has

elongated and is nearly finished
dividing
• Cell-like features begin to reappear
such as the reformation of two
nuclei (one for each cell)
• The chromosomes then de-
condense and the mitotic spindle
fibres are broken down
David O Morgan - The Cell Cycle. Principles of Control.

Cytokinesis
• Cytokinesis is the division of the

cytoplasm to form two new cells
• This stage actually begins between
anaphase and telophase, however,
doesn’t finish until after telophase
• To separate the two cells, a ring of
protein (actin ring) pinches the
cytoplasm along a crease known as
a cleavage furrow
• This splits the cytoplasm equally
between the two cells
David O Morgan - The Cell Cycle. Principles of Control.

Cell cycle and checkpoints
Mitosis
• In cell biology, mitosis is a part of the cell
cycle in which replicated chromosomes are
separated into two new nuclei
• Cell division by mitosis gives rise to
genetically identical cells in which the total
number of chromosomes is maintained
https://www.genome.gov/genetics-glossary/Meiosis
Chromosome movements in meiosis
Sperm and egg production in human
• Cell division of germ cells in sexually-
reproducing organisms that produces
Meiosis the gametes, such as sperm or egg cells
• It involves two rounds of division that
ultimately result in four cells with only
one copy of each chromosome
(haploid)
• Meiosis I: the ploidy is reduced from
diploid to haploid, thus is referred to as
a reductional division
• Meiosis II: an equational division
analogous to mitosis, in which the sister
chromatids are segregated, creating
four haploid daughter cells
Course outline:
d. Complex diseases

6. Cancer Genetics
Objectives
• Distinguish the three types of DNA mutations: genome, chromosomal, and

gene
• Describe chromosomal compaction and the proteins involved in chromatin
structure
• Diagram a human chromosome, and label the centromere, q arm, p arm,
and telomere
• Illustrate the different types of structural mutations that occur in
chromosomes
• State the karyotype of a normal male and female
• Identify the chromosomal abnormality in a given karyotype
• Compare and contrast interphase and metaphase FISH analyses
• Compare and contrast FISH and CGH
Human genome
• All of the genes found in a single individual

• 2.9 billion nucleotide base pairs in 23 chromosomes
inherited from each parent
• 46 chromosomes
• humans have two copies of every gene (except for some on
the X and Y chromosomes
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
Mutation, variant and polymorphism
• A transmissible (inheritable) change in the DNA sequence is a mutation or

polymorphism
• A DNA sequence change that is present in a relatively small proportion of a
population is a mutation
• The term variant may also be used, particularly to describe inherited
sequence alterations, thus reserving the term mutation for somatic
changes, for example, changes found only in tumor tissue
• A change in the DNA sequence that is present in at least 1% to 2% of a
population is a polymorphism
• Both mutations and polymorphisms may or may not produce phenotypic
differences.
DNA mutation (Gene mutation, Chromosome mutation)
• DNA mutations can affect a single nucleotide or millions of

nucleotides, even whole chromosomes, and thus can be classified
into three categories: gene, chromosome, and genome mutations
• Gene mutations affect single genes and are often, but not always,
small changes in the DNA sequence
• Chromosome mutations affect the structures of entire
chromosomes These changes require movement of large
chromosomal regions (hundreds of thousands to millions of base
pairs) either within the same chromosome or to another
chromosome
DNA mutation (Genome mutation)
• Genome mutations are changes in the number of

chromosomes
• A cell or cell population with a normal complement of
chromosomes is euploid
• Genome mutations result in cells that are aneuploid
• Aneuploidy is usually (but not always) observed as increased
numbers of chromosomes, because the loss of whole
chromosomes is not compatible with survival
DNA mutation (Genome mutation)
• A single copy of each chromosome (23 in humans) is a haploid

complement
• Humans are normally diploid, with two copies of each
chromosome
• Aneuploidy can result when there are more than two copies of a
single chromosome or when there are multiple copies of one or
more chromosomes
• Down syndrome is an example of a disease resulting from
aneuploidy, where there are three copies of chromosome 21 i.e.
Trisomy 21 or T21
Chromosomes are visible during mitosis
Human chromosome
Morphology of chromosomes
Chromosome nomenclature
DNA compaction into metaphase
chromosomes
DNA wrapped around eight histone proteins

(two each of histone 2A, 2B, 3, and 4) forms a nucleosome
Karyotyping
• Genome mutations, or
aneuploidy, can be detected
directly by karyotyping
• A karyotype is the complete set
of chromosomes in a cell
• Karyotyping is the direct
observation of metaphase
chromosome structure by
arranging metaphase
chromosomes according to size
https://le.ac.uk/vgec/topics/cell-cycle/the-cell-cycle-
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis. higher-education
Karyotyping
• It requires collecting living cells and growing them in culture in the

laboratory for 48 to 72 hours
• Cell division is stimulated by addition of a mitogen, usually
phytohemagglutinin
• Dividing cells are then arrested in metaphase with colcemid, an inhibitor
of microtubule (mitotic spindle) formation
• The chromosomes in dividing cells that arrest in metaphase will yield a
chromosome spread when the cell nuclei are disrupted with hypotonic
saline
• The 23 pairs of chromosomes can then be assembled into an organized
display, or karyotype, according to their size and centromere placement
Supplementary video
• https://www.youtube.com/watch?v=1tDE3TBROUI
(something differs from routine practice)
• Short term culture
• Non synchronize culture (NS): Incubate at 37 C and 5% CO 2 overnight
• Synchronize culture (S):
• Blocking agent (At 17:00 before the day of harvest): 5-fluorodeoxyuridine +
Uridine for 16-20hrs
• Mechanism for action: antagonist to thymidylate synthetase, so no dTMP production, cell cycle blocked at DNA
synthesis phase (S phase)
• Releasing agent (At 9:00 of the following day): Thymidine for 6hrs (Time
required for cells to complete the S phase, G2 phase and reach Metaphase)
• Trypsin is used instead of thymidine prior Giemsa or Leishman staining
Banding patterns of individual chromosomes
(Giemsa staining) cytogenetics to produce a visible karyotype by
Giemsa banding is a technique used in
staining condensed chromosomes.

Metaphase spread to generate karyotyping
image
A normal male karyotype
• There are 22 sets of autosomes, one inherited from each

parent, and one pair of sex chromosomes, XY
• This karyotype is designated 46, XY
Buckingham, L. (2019). Molecular diagnostics:

fundamentals, methods and clinical applications. FA
Davis.
A karyotype of a Down syndrome patient (47, XX,+21)
Ponnuraj, K. T. (2011). Cytogenetic techniques in diagnosing genetic disorders. Advances in the study
of genetic disorders. Croatia InTech, 45-64.
Identification of chromosomal location by
G-band patterns
• The long arm of a chromosome is

designated q, and the short arm is telomere
designated p.
centromere
telomere
Karyotyping-chromosomal mutation detection (translocations)
• Translocations: the exchange of genetic material between chromosomes

• Reciprocal translocations: parts of two chromosomes exchange; that is, each
chromosome breaks and the broken chromosomes reassociate or recombine with
one another
• When this type of translocation does not result in gain or loss of chromosomal material,
it is balanced. Balanced translocations may occur, therefore, without phenotypic effects.
• Balanced translocations in germ cells (cells that give rise to eggs or sperm) can, however,
become unbalanced by not assorting properly during meiosis; as a result, they affect the
phenotype of offspring
• A robertsonian translocation involves the movement of most of one entire
chromosome to the centromere of another chromosome
• This type of translocation may also become unbalanced during reproduction, resulting in
a net gain or loss of chromosomal material in the offspring
Balanced reciprocal translocation &
Robertsonian translocation
A balanced reciprocal translocation A robertsonian translocation
Karyotyping-chromosomal mutation detection (deletion,
insertion and inversion)
• Deletion: a loss of chromosomal material

• Insertion: a gain of chromosomal material
• The inserted sequences arise from duplication of particular
regions within the affected chromosome or from fragments of
other chromosomes
• Inversion: result from excision, flipping, and reconnecting
chromosomal material within the same chromosome
Karyotyping-chromosomal mutation detection (Other types)
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods

and clinical applications. FA Davis.
Fluorescence In Situ Hybridization (FISH)
A. Interphase FISH Fluorescence in situ hybridization

• is a method widely used to detect protein and RNA as well as DNA structures in
place in the cell, or in situ
• FISH offers a more rapid assay with higher resolution and flexibility than
karyotyping
• Interphase FISH does not require culturing of cells, and metaphase
• FISH allows detection of much smaller regional abnormalities than are visible
by karyotyping
• Since growing cells in culture is not required, interphase FISH methods are used
commonly to study prenatal samples, tumors, and hematological malignancies,
not all of which are conveniently brought into metaphase in culture
Fluorescence In Situ Hybridization
• For FISH cytogenetic analysis, fixed cells are exposed to a probe

• The probe is a covalently to a fluorescent molecule
• The probe will hybridize, or bind, to its complementary sequences in
the cellular DNA
• In interphase FISH, the bound probe is visualized under a fluorescent
microscope as a point of fluorescent light in the nucleus of the cell
• Probes are designed to be complementary to a particular
chromosome or chromosomal locus so that the image under the
microscope will correlate with the state of that chromosome or locus
Aneuploidy detection by FISH
• For example, a probe to any unique region on chromosome 22

should yield an image of two signals per nucleus, reflecting the
two copies of chromosome 22 in the somatic cell nucleus
• A deletion or duplication of the DNA that is hybridized to the
probe will result in a nucleus with only one signal or more than
two signals, respectively
Translocation detection by FISH
Fluorescence In Situ Hybridization (FISH)
B. Metaphase FISH
• fluorescent probes that bind to metaphase chromosomal regions or to whole
chromosomes
• detect small or complex rearrangements that are not apparent by regular
chromosome banding
• By mixing combinations of different fluors and using special imaging software,
spectral karyotyping can distinguish all 23 chromosomes by chromosome-specific
colors
Shen, C. H. (2019). Diagnostic molecular biology. Academic Press.
• Telomeric and centromeric probes are also applied to metaphase chromosomes to

detect aneuploidy and structural abnormalities
Spectral Karyotyping (SKY)
Shen, C. H. (2019). Diagnostic molecular biology. Academic Press.

Comparative genomic hybridization (CGH)
Array CGH
Conventional CGH
Comparative genomic hybridization (CGH) is a molecular cytogenetic method for analysing
copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to
a reference sample, without the need for culturing cells
• The aim of this technique is to quickly and efficiently compare two genomic DNA samples
arising from two sources, which are most often closely related, because it is suspected that
they contain differences in terms of either gains or losses of either whole chromosomes or
subchromosomal regions (a portion of a whole chromosome)
• This technique was originally developed for the evaluation of the differences between the
chromosomal complements of solid tumor and normal tissue, and has an improved
resolution of 5–10 megabases compared to the more traditional cytogenetic analysis
techniques of giemsa banding and fluorescence in situ hybridization (FISH) which are
limited by the resolution of the microscope utilized
https://www.youtube.com/watch?v=MMkYSWzOwrY
This is achieved through the use of competitive fluorescence in situ hybridization
• In short, this involves the isolation of DNA from the two sources to be compared, most
commonly a test and reference source, independent labelling of each DNA sample with
fluorophores (fluorescent molecules) of different colours (usually red and green),
denaturation of the DNA so that it is single stranded, and the hybridization of the two
resultant samples in a 1:1 ratio to a normal metaphase spread of chromosomes, to which
the labelled DNA samples will bind at their locus of origin
• Using a fluorescence microscope and computer software, the differentially coloured
fluorescent signals are then compared along the length of each chromosome for
identification of chromosomal differences between the two sources
• A higher intensity of the test sample colour in a specific region of a chromosome indicates
the gain of material of that region in the corresponding source sample, while a higher
intensity of the reference sample colour indicates the loss of material in the test sample in
that specific region
• A neutral colour (yellow when the fluorophore labels are red and green) indicates no
difference between the two samples in that location
CGH is only able to detect unbalanced chromosomal abnormalities
• This is because balanced chromosomal abnormalities such as reciprocal translocations,
inversions or ring chromosomes do not affect copy number, which is what is detected by
CGH technologies
• CGH does, however, allow for the exploration of all 46 human chromosomes in single test
and the discovery of deletions and duplications, even on the microscopic scale which may
lead to the identification of candidate genes to be further explored by other cytological
techniques
• Through the use of DNA microarrays in conjunction with CGH techniques, the more specific
form of array CGH (aCGH) has been developed, allowing for a locus-by-locus measure of
CNV with increased resolution as low as 100 kilobases.
• This improved technique allows for the aetiology of known and unknown conditions to be
discovered
Array CGH
FISH vs CGH
https://www.differencebetween.com/difference-between-fish-and-cgh/#FISH%20vs%20CGH
%20in%20Tabular%20Form
Integrated FISH, Karyotyping and aCGH Analyses for Effective Prenatal Diagnosis
of Common Aneuploidies and Other Cytogenomic Abnormalities
Course outline:
d. Complex diseases

6. Cancer Genetics
Types of chromosome abnormalities
• Numerical abnormalities
• Structural abnormalities
i. Unbalanced rearrangements
ii. Balanced rearrangements
Chromosomal instability
Vargas-Rondón, N. et.al. (2017) Cancers. 10(1), 4.DOI:10.3390/cancers10010004

Incidence of chromosomal abnormalities in newborns
Type of abnormality Approximate incidence
Sex chromosome abnormalities in males
47,XXY 1/1080 male births
47,XYY 1/1080
Other 1/1350
Total 1/385
Sex chromosome abnormalities in females
45,X 1/9600 female births
47,XXX 1/960
Other 1/2740
Total 1/660
Autosomal numerical abnormalities in infants
Trisomy 21 1/800 live births
Trisomy 18 1/8140
Trisomy 13 1/19 000
Triploidy 1/57 000
Total 1/695
Structural abnormalities in infants (autosomes and sex
chromosomes)
Balanced rearrangements
Robertsonian 1/1120 live births
Other 1/965
Unbalanced rearrangements 1/1675
Total 1/395
All chromosome abnormalities 1/160 live births
(autosomes and sex chromosomes)
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn. Luthardt, F.W. & Keitges, E. (2001)
WB Saunders. Encyclopedia of Life Sci , 1–12.
Clinical features of patients with common autosomal or sex chromosome aneuploidy
Syndrome Karyotype Main clinical features

Down Trisomy 21 Short, broad hands with single palmar crease, decreased muscle tone, mental
retardation, broad head with characteristic features, open mouth with large tongue,
up-slanting eyes
Edwards Trisomy 18 Multiple congenital malformations of many organs, low-set malformed ears, receding
mandible, small eyes, mouth and nose with general elfin appearance, severe mental
deficiency, congenital heart defects, horseshoe or double kidney, short sternum,
posterior heel prominence
Patau Trisomy 13 Severe mental deficiency, small eyes, cleft lip and/or palate, extra fingers and toes,
cardiac anomalies, midline brain anomalies, genitourinary abnormalities
Turner 45,X Female with retarded sexual development, usually sterile, short stature, webbing of
skin in neck region, cardiovascular abnormalities, hearing impairment, normal
Klinefelter 47,XXY intelligence
Male, infertile with small testes, may have some breast development, tall, mild
Triple X 47,XXX mental deficiency, long limbs, at risk for educational problems
Female with normal genitalia and fertility, at risk for educational and emotional
XXY 47,XYY problems, early menopause
Tall male with normal physical/sexual development, normal intelligence, increased
tendency for behavioural and psychological problems
Luthardt, F.W. & Keitges, E. (2001)

Encyclopedia of Life Sci , 1–12.
Frequency of Down syndrome (number of cases per 100 live births) related to age of mother
Incidence
10.0
At amniocentesis
Maternal age (years) At birth (16 weeks)
15–19 1/1250 –
3.0 20–24 1/1400 –
2.0 25–29 1/1100 –
Syndrome (percentage of
30 1/900 –
1.0 33 1/625 1/420
Incidence of Down
34 1/500 1/325
35 1/350 1/250
live births)
36 1/275 1/200
0.3
37 1/225 1/150
0.2
38 1/175 1/120
39 1/140 1/100
0.1
40 1/100 1/75
45 and over 1/25 1/20
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn.
0.03 WB Saunders.
15 20 25 30 35 40 45 50
Maternal Age
(years)
Hook EB, Lindsjö A. American Journal of Human Genetics. 30:19; 1978.

Maternal age-related frequency of aneuploid fetuses detected prenatally
Aneuploid rate per 1000

Maternal age range (years) Total number of fetuses Trisomy 21 Trisomy 18 Trisomy 13 XXX XXY XYY
35–49 19 672 9.1 2.5 0.6 1.0 1.3 0.5
Modified from Schreinemachers et al. (1982) Human Genetics 61: 318–324.
Rate per 1000

All chromosome
Age Trisomy 21 Trisomy 18 Trisomy 13 XXX XXY anomalies
35 3.9 0.5 0.2 0.6 0.5 8.7
36 5.0 0.7 0.3 0.7 0.6 10.1
37 6.4 1.0 0.4 0.7 0.8 12.2
38 8.1 1.4 0.5 0.8 1.1 14.8
39 10.4 2.0 0.8 1.2 1.4 18.4
40 13.3 2.8 1.1 1.5 1.8 23.0
41 16.9 3.9 1.5 1.8 2.4 29.0
42 21.6 5.5 2.1 2.4 3.1 29.0
45 44.2 – – 18.0 7.0 62.0
Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright. Encyclopedia of Life Sci , 1–12.
Common autosomal trisomies
- Down Syndrome (47, +21)
(b)
Cummings, M.R. (2010) Human Heredity: Principles and issues.

Common sex chromosome abnormalities (I)
- 45, X Turner Syndrome (monosomy X or XO female)
• Female with retarded sexual
development (usually sterile)
• short stature
• webbing of skin in neck
region
• cardiovascular abnormalities
• hearing impairment
• normal intelligence
Luthardt, F.W. & Keitges, E.

(2001)
Common sex chromosome abnormalities (II)
- Klinefelter syndrome (47, XXY male)

- 47, XYY syndrome (male)
- Trisomy X syndrome (47, XXX female)
Chromosome structural rearrangements Isochromosom
Ring
chromosome
with two acentric
e generation fragments
for short and
Termina Interstitia Pericentric Paracentric Direct Inverted
long arms
l l inversion inversion duplicatio duplicatio
deletion deletion n n
Reciprocal translocation
Insertion of segment with exchange of Robertsonian
from one segments between translocation
Balanced rearrangements
chromosome into a nonhomologous between two
nonhomologous chromosomes acrocentric
chromosome chromosomes

(2001)
Common autosomal deletions
Syndrome Chromosome region deleted Main clinical features
Wolf–Hirschhorn 4p16.3 Severe growth retardation, midline facial defects, mental retardation,
small head, prominent frontal bone between eyebrows, cleft lip/
palate, cardiac defects, wide-spaced eyes, broad nasal bridge
Cri du chat 5p15.2 High-pitched cry, wide-spaced eyes, small chin, small head, round
face, severe psychomotor and mental retardation
Langer–Giedion 8q24.11-q24.13 Small head, mental retardation, sparse hair, bulbous nose, short
stature, multiple cartilaginous growths on bone surfaces
Data from various sources.

(2001)
Common autosomal deletions
- Wolf-Hirschhorn Syndrome (4p deletion)
- Cri du chat (5p deletion)
Both syndromes have

severe learning difficulties
A child with deletion 4p syndrome—Wolf- Hirschhorn Facial view of a 2-year-old boy with cri-du-chat syndrome.
syndrome.
Autosomal microdeletion syndromes
Chromosome
Syndrome region Incidence Main clinical features
Williams 7q11.23 1/20 Cardiac anomalies, mental retardation, characteristic facies, growth
000 retardation, gregarious disposition, connective-tissue problems
WAGR 11p13 Kidney tumour, absence of iris, genital abnormalities, growth retardation
Prader–Willi 15q11.2 1/10 Developmental delay, mental retardation, decreased muscle tone,
000 obesity,
Angelman 15q11.2 1/10 small genitals, excessive appetite, hypopigmentation
000 Developmental delay, mental retardation, unstable gait, absence of
Miller–Dieker 17p13.3 speech, hyperactivity, spontaneous laughter, hypopigmentation
Smith–Magenis 17p11.2 1/25 Smooth brain, small head, small chin, growth failure, cardiac
000 abnormalities
Flat midface, wide head, broad nasal bridge, short fingers and toes,
Alagille 20p11.23-p12.2 mental retardation, hyperactivity, short stature, characteristic
behavioural problems
Catch 22 22q11.2 Chronic bile flow suppression, dysmorphic facies, ring-like corneal
opacity, vertebral arch defects, narrowing of heart opening
DiGeorge 22q11.2 1/5000 Cardiac defects, abnormal facies, underdeveloped thymus, cleft
palate, decreased calcium in blood
Velocardiofacial 22q11.2 Underdeveloped thymus and parathyroid glands, facial
abnormalities, cardiac defects
Cleft palate, Luthardt,
abnormal F.W. & Keitges,
nose, E. (2001) delay,
developmental Encyclopedia
cardiac of Life Sci , 1–12.
abnormalities
Autosomal duplication syndromes
Chromosome
Syndrome region duplicated Main clinical features
Beckwith–Wiedemann 11p15.5 Large tongue, tissue and organ overgrowth, mild mental retardation
Charcot–M arie–Tooth 17p11.2-p12 Decreased reflexes, progressive distal muscular wasting, decreased
disease type 1A muscle tone, sensory neuropathy
Cat-eye 22pter-q11.2 Eye defects, absence of anal opening, skin tags in front of ears,
characteristic facies, renal, skeletal and genital anomalies, mental
retardation
Data from various sources.

Risks of unbalanced offspring for rearrangement carriers
Percentage
of unbalanced
Type of rearrangement offspring
Robertsonian translocations
14/21, female 10–15
14/21, male 13/14, 2–5
both sexes 1–2
21/22, female 10–15
21/22, male 1–2
21/21 both 100
sexes
Reciprocal
Pooled, both sexes 6–12
translocations
Ascertained by unbalanced child 20
Ascertained by unbalanced child with 50
small unbalanced segment
Other ascertainment 2–5
t(11;22)(q23;q11.2) 5–7
Recurrence risk unbalanced t(11;22) 2
Pericentric inversions
Ascertained by unbalanced child 5–10
Other ascertainment 2
Modified from Nora and Fraser (1993) Medical Genetics: Principles
and Practices, 4th edn. Lea and Febiger. Encyclopedia of Life Sci , 1–12.
Summary:
• Cytogenetics studies the number and morphology of

chromosomal abnormality associating with diseases
• Karyotyping, FISH and aCGH can be employed for prenatal

diagnosis of common aneuploidies and other cytogenomic
abnormalities
• Chromosomal abnormalities lead to genetic material

changes and appear in number of diseases in development

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BIOL-S402F Medical Genetics and Immunology

(Part B: Medical Genetics)

By Dr. Andy YY CHEUNG

5. Genetics in Diseases and Development

the cell grows (G1)

replicates its DNA (S)

• The first and longest phase of

Formation of the mitotic spindle

Beginning of nucleoli breakdown

• In this stage, the chromosomes

• At this stage, the chromosomes

• At this stage, the cell will check

• During this stage, sister chromatids

• In this phase, the cell has

David O Morgan - The Cell Cycle. Principles of Control.

• Cytokinesis is the division of the

David O Morgan - The Cell Cycle. Principles of Control.

5. Genetics in Diseases and Development

• Distinguish the three types of DNA mutations: genome, chromosomal, and

• All of the genes found in a single individual

• A transmissible (inheritable) change in the DNA sequence is a mutation or

• DNA mutations can affect a single nucleotide or millions of

• Genome mutations are changes in the number of

• A single copy of each chromosome (23 in humans) is a haploid

DNA wrapped around eight histone proteins

• It requires collecting living cells and growing them in culture in the

staining condensed chromosomes.

• There are 22 sets of autosomes, one inherited from each

Buckingham, L. (2019). Molecular diagnostics:

• The long arm of a chromosome is

• Translocations: the exchange of genetic material between chromosomes

A balanced reciprocal translocation A robertsonian translocation

• Deletion: a loss of chromosomal material

Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods

A. Interphase FISH Fluorescence in situ hybridization

• For FISH cytogenetic analysis, fixed cells are exposed to a probe

• For example, a probe to any unique region on chromosome 22

Shen, C. H. (2019). Diagnostic molecular biology. Academic Press.

• Telomeric and centromeric probes are also applied to metaphase chromosomes to

Shen, C. H. (2019). Diagnostic molecular biology. Academic Press.

5. Genetics in Diseases and Development

Vargas-Rondón, N. et.al. (2017) Cancers. 10(1), 4.DOI:10.3390/cancers10010004

Syndrome Karyotype Main clinical features

Luthardt, F.W. & Keitges, E. (2001)

Hook EB, Lindsjö A. American Journal of Human Genetics. 30:19; 1978.

Aneuploid rate per 1000

Rate per 1000

Cummings, M.R. (2010) Human Heredity: Principles and issues.

Luthardt, F.W. & Keitges, E.

- Klinefelter syndrome (47, XXY male)

Luthardt, F.W. & Keitges, E.

Luthardt, F.W. & Keitges, E.

Both syndromes have

Luthardt, F.W. & Keitges, E. (2001)

• Cytogenetics studies the number and morphology of

• Karyotyping, FISH and aCGH can be employed for prenatal

• Chromosomal abnormalities lead to genetic material

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