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Clinical Cytogenetics: The Chromosomal Basis of Human Disease

This document discusses various types of chromosome abnormalities including abnormalities in chromosome number, structure, and sex chromosomes. It covers topics like aneuploidy involving extra or missing chromosomes, translocations, deletions, duplications, ring chromosomes, inversions, and isochromosomes. It also discusses how these abnormalities can cause conditions like Down syndrome, Turner syndrome, Klinefelter syndrome, and how they relate to pregnancy loss and birth defects.

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Gia Hoàng
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90 views45 pages

Clinical Cytogenetics: The Chromosomal Basis of Human Disease

This document discusses various types of chromosome abnormalities including abnormalities in chromosome number, structure, and sex chromosomes. It covers topics like aneuploidy involving extra or missing chromosomes, translocations, deletions, duplications, ring chromosomes, inversions, and isochromosomes. It also discusses how these abnormalities can cause conditions like Down syndrome, Turner syndrome, Klinefelter syndrome, and how they relate to pregnancy loss and birth defects.

Uploaded by

Gia Hoàng
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Clinical Cytogenetics: The

Chromosomal
Basis of Human Disease
Le Minh Thong PhD.
Chromosome abnormalities

• 1 of every 150 live births


• Leading cause of intellectual disability and pregnancy loss
• Seen in 50% of first-trimester and 20% of second-trimester
spontaneous abortions
• Specific genes can affect cytogenetic phenotypes
In this chapter:
• Abnormalities of chromosome
• Number
• Structure
• Sex chromosome abnormalities
• Cancer
• Other disease
• New technology in cytogenetics
CYTOGENETIC TECHNOLOGIES
46,XY,t(7;10)(p22;q23)

• Put the root tip in acid


• Soak in the dye
• Press on the slide
• Watch under microscope

https://www.youtube.com/watch?v=E0WkZr819UU
Partial trisomy of the distal part of 10q: A report of two Egyptian cases
Karyogram and karyotyping
• To identify the number, shape and size of chromosomes of
cells

Medical dictionary
Karyotyping: other cases
Chromosome banding techniques
Q Banding
Solid Staining

R Banding

G Banding
Other selective staining techniques
C (centromere) Banding Silver Staining

High Cytogenic Resolution Banding

Prophase cells
Band level: ~ 500 -> 800 bands
Resolution: 2 – 3 Mb < 5 Mb
Karyotype nomenclature

• By Size
• By band pattern
• By centromere pattern
• Metacentric
• Acrocentric
• Sub-metacentric
Karyotype nomenclature
Karyotype nomenclature
• Male: 46,XY
• Female: 46,XX
• Region:
• 14q32: second band in the third region of the long arm of
chromosome 14
Fluorescence in Situ Hybridization (FISH)

• Can use metaphase,


prophase and interphase
(faster, no need to culture
cell)
• Higher resolution: ~ 1 Mb
• Detect delete and extra
chr/region
• Multiplex ~ spectral
karyotyping
Small arrow: Chr 17
Large arrow: 17p
Spectral karyotyping
Comparative Genomic Hybridization

• Array CGH:
• High resolution 50 – 100 kb or only one gene
• No need culture cell
• Less required DNA
Chromosome abnormalities
• Chromosome number
• Polyploidy
• Triploidy
• Tetraploidy
• Aneuploidy
• Autosome: Trisomy 13, 18, 21
• Sex chromosome aneuploidy:
X-, XXY, XXX
• Chromosome structure:
• Translocation: balance,
unbalance
• Deletion
• …..
Polyploidy
• Triploidy: 69,XXX (Y also)
• Rate: 1/10000 in birth but
15% in conception: loss at 2
first trimesters
• Shortly died
• Almost by dispermy Triploidy
• Also by using a polar body
• Or by meiotic failure
• Tetraploidy: 92,XXXX (Y also)
• Very rare in birth or
conception
• Short life
• Caused by meiotic failure

Mosaic triploidy
Tetraploidy

15 months old baby with tetraploidy


Autosomal aneuploidy
• Aneuploidy = not euploidy (23 chr x 1 or 2 or 3 or 4 …)
• Usually only one chromosome affected
• Missing – monosomy
• Extra (duplicated) – trisomy
• Common cause: Nondisjunction in meiosis I or II
• Autosomal aneuploidy normally die except:
• Trisomy 13, 18, 21
• But not monosomy
Nondisjunction in meiosis
Down syndrome – Trisomy 21

John Langdon Down – 1866


Down syndrome
• Prevalence: 1/700
• Characteristic appearance of the face
• Short neck, limp (and flat)
• Hypotonia (decrease muscle tone)
• 3% closure or absence of anus
• 40% heart defect
• IQ 40 – 60
• 20 time higher leukemia
• Infertile in male
• ~ 95% due to mother extra chr
• 2- 4% mosaicism – tissue specific
• Important gene: DYRK1A - a kinase gene that causes learning and memory defects
when it is over-expressed
“Lastly, a recent clinical trial has shown that
epigallocatechine gallate (EGCG), a DYRK1A inhibitor, given
to young patients with DS improved visual recognition
memory, working memory performance and adaptive
behaviour.”
Edwards syndrome – Trisomy 18
• Trisomy 18 (47,XY,+18)
• Prevalence 1/6000 ~ 5% of cases from conceptus (95% died, stillborn)
• Characteristic facial features
• Heart defect
• ~ 50 % die at first year
• Only ~ 8% get to 12 year olds
Patau syndrome – Trisomy 13
• Trisomy 18 (47,XY,+18)
• Prevalence: 1/10000
• Malformation at nervous system
• Heart defect
• 95% die at 1st year
• Due to mother site
Trisomies, Nondisjunction, and Maternal Age

• Increase in nondisjunction
among older mothers
• Nearly all of a female’s oocytes
are formed during her
embryonic development (45
year old female have 45 year old
eggs)
• Other factors (but not clear in
human):
• Hormone level
• Cigarette
• Alcohol
• Radiation
Sex Chromosome Aneuploidy:
Monosomy of the X Chromosome (Turner
Syndrome)
• 45,X, women
• Short stature, sexual infantilism (less 20 cm)
• Triangle-shaped face
• Webbing of the neck
• Chest is broad and shield-like Henry Turner 1938
described the disease
• Congenital heart, kidney defect
• Normal intelligence
• Infertile (Some have baby)
• Hormone therapy (growth hormone, estrogen)
• 40% have mosacism (45,X/46,XX >> 45,X/46,XY)
• 60 - 80% of monosomy due to the lacking X chr in
sperm
• 1 - 2% of conception but seen 1/2000 - 1/3000
(99% died in conception)
• Main gene: SHOX (expressed on X and Y short tip)
Klinefelter Syndrome - 47,XXY - male

• 1/500 to 1/1000 male births


Described the
• taller than average syndrome in 1942
• long arms and legs
• small testes (10 ml in vol)
• sterile
• 1/3 developed breast => cancer Harry Klinefelter
• Normal intelligence
• 15 % mosaicism
• Also 48,XXXY; 49,XXXXY (more X
more severe)
• Testosterone theraphy
Trisomy X - 47,XXX - female

• 1/1000
• benign consequences
• sometimes have sterility
• mild cognitive disability
• Due to nondisjunction from mother
• More X more severe

Wiki
47,XYY Syndrome -male

• Taller than average


• Reduce IQ
• Incidence in the male prison
population (1/30 >> 1/1000)
• Behavioral disorders: hyperactivity,
attention deficit, learning
disabilities.
CHROMOSOME ABNORMALITIES AND PREGNANCY
LOSS
• Spontaneous pregnancy loss is common in humans (1/3, after
implantation)
• 10 – 20% abnormalities in chromosome => 95 % lost before term
• 50 % trisomy (trisomy 16 is most common, but never come)
• 20 % monosomy
• 15 % triploids
• Remain: tetraploids & structure abnormalities

• How about gametes?


• Egg (from unused IVF): 20 – 25% missing or extra, 1% structure abnormalities
• Sperm (fused with hamster egg  condensed): 3 – 4%, 5 % structure abnormalities
• Incidence increased follow age
ABNORMALITIES OF CHROMOSOME STRUCTURE

• Balance
• Unbalance
• Cause
• Unequal crossover
• Chromosome breakage during
meiosis
• Ionizing
• Radiation
• Viral infection
• Other chemicals
Translocation: Reciprocal Translocations

• Mutually exchange between non-


homologous chromosomes
• The carrier normally normal
• The offspring:
• Normal
• Duplication – partial trisomy
• Deletion
Translocation: Robertsonian Translocations

• Short arm loss and long arm fuse to


single chromosome
• Occur in acrocentric chromosome
(13, 14, 15, 21, 22)
• Usually no harm: short arm less
materials
• The carrier: 45 chromosomes in
cell, unaffected
• The offspring: extra (Down) or
missing long arm of acrocentric
chromosome
• Most common 45,XY or
XX,der(14;21)(q10;q10)
Deletions

• Terminal deletion
• Interstitial deletion
• Loss materials ~ several genes
(microscopy abservable)
• Example: Cri-du-chat syndrome
• Distal short arm of chromosome 5
• 46,XY,del(5p)
• 1 in 50,000 live births
• Intellectual disability (IQ 35)
• Abnormal crying
• Normal apperrance
Microdeletion Syndromes
• Detected by high resolution FISH or aCGH (< 5 Mb)
• Example: Prader–Willi syndrome 70% cases caused by microdeletions of
15q
• Also microduplication
• Caused by multiple repeated sequences at boundary of the dup/del
Subtelomeric Rearrangements
• High density of genes in telomere
• Telomeric rearrangement normally causes disease
• Most common 1p36 deletion (monosomy) (1/5000 births) =>
intellectual disability, developmental delay, seizures, hearing
impairment, heart defect
Uniparental Disomy

• 30 % cases of Prader-Willi syndrome


• Abnormal imprinting (both copies imprinted and not expressed)
Duplications
• Seen in offspring of reciprocal translocation carriers
• Unequal crossover during meiosis
• X-linked color vision loci
• Produce less serious consequences
Ring Chromosomes

• Deletion in both chromosome tips and ligate


to the ring
• Ring structure is not favored in mitosis =>
loss in some cell  monosomy mosaicism
• Any chromosome can be ring, most
common: 14 and 22 chr

46,X,r(X)
Inversions
• Due to 2 breaks of chromosomes
and reinsertion by repair system
• Pericentric inversion (with
centromere)
• Paracentric inversions (without
centromere)
• Example: inversion that interrupts
the factor VIII gene produces
severe hemophilia A
• Other consequences: Induce
deletion or duplication in meiosis
Isochromosomes
• Wrong axis devide of chromosome
propagation or Robertsonian translocation
• Autosome – lethal
• Seen in X isochromosome
• (46,X,i[Xq]: Turner
CANCER CYTOGENETICS
• Take place in somatic cell
• chronic myelogenous leukemia (CML): reciprocal translocation between
chromosomes 9 and 22  increase tyrosine kinase
• And more than 100 rearrangement for 40 type of human cancers
CHROMOSOME INSTABILITY SYNDROMES

• Chromosome very easy to be breaked


• May relate to repair system defect
•  induce cancer
• Many protein encoded by nuclear genes and go to mitochondria, how
about mitochondria situation in case of polyploid peoples?
• Why many chromosome abnormalities lead to heart defect
• How to detect mosacism?

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