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Cytogenetics

This document discusses cytogenetics and chromosome abnormalities. It begins with basic definitions like karyotype and chromosome banding. It then discusses numerical abnormalities such as aneuploidy and nondisjunction. Structural abnormalities like translocations, deletions, inversions, and ring chromosomes are also covered. Advances in molecular cytogenetics including fluorescence in situ hybridization (FISH) and spectral karyotyping are described for detecting chromosome abnormalities.

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150 views28 pages

Cytogenetics

This document discusses cytogenetics and chromosome abnormalities. It begins with basic definitions like karyotype and chromosome banding. It then discusses numerical abnormalities such as aneuploidy and nondisjunction. Structural abnormalities like translocations, deletions, inversions, and ring chromosomes are also covered. Advances in molecular cytogenetics including fluorescence in situ hybridization (FISH) and spectral karyotyping are described for detecting chromosome abnormalities.

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Nguyễn Thu
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CYTOGENETICS

Tran Thi Kim Van, MD


Medical Genetics Institute
Learning Objectives

1. Interpret scenarios about basic definitions and terminology

2. Solve problems concerning numerical chromosome abnormalities

3. Demonstrate understanding of structural chromosome abnormalities

4. Solve problems concerning advances in molecular cytogenetics


BASIC DEFINITIONS AND TERMINOLOGY

• Karyotype: an ordered display of the 23 pairs of human


chromosomes in a typical somatic cell
Chromosome banding

• G-banding: mitotic chromosomes are


partially digested with trypsin, then
stained with Giemsa.

• Light and dark regions

• Can identify some chromosome


abnormalities (resolutions #4Mb)
Chromosome nomenclature
NUMERICAL CHROMOSOME ABNORMALITIES

Euploidy:

• A cell has a multiple of 23 chromosomes: Haploid, diploid


• Triploidy: contain 3 copies of each chromosome (69 total)
• Tetraploidy: contain 4 copies of each chromosome (92 total)

Aneuploidy:
• gain (+) or loss (-) of a specific chromosome
• Monosomy, Trisomy
Aneuploidy (cont)
• Autosomal aneuploidy:
- All autosomal monosomies are inconsistent with a live birth.
- Only 3 autosomal trisomies (trisomy 13, 18, and 21) are consistent with a live birth
(Patau, Edward, Down syndrome)
• Sex chromosome aneuploidy:
- At least one X chromosome is required for survival.
- If a Y chromosome is present, the phenotype is male (with minor
exceptions).
- If more than one X chromosome is present, all but one will become a
Barr body in each cell.
- Ex: Turner syndrome and Klinefelter syndrome.
Genetic Mosaicism in Turner Syndrome
• Genetic mosaicism is defined as a condition in
which there are cells of different genotypes or
chromosome constitutions within a single
individual.

• Some women with Turner syndrome have


somatic cells that are 45,X and others that are
46,XX or 47,XXX.

• is thought to arise in early embryogenesis by


mechanisms that are not completely
understood.
Nondisjunction

• Nondisjunction is the usual cause of aneuploidies including Down,


Edward, Patau, Turner, and Klinefelter syndromes.
• More likely to occur during oogenesis than during spermatogenesis.
• More likely with increasing maternal age. Environmental agents (e.g.,
radiation, alcohol) appear to have no measurable influence.
• More likely in meiosis I than meiosis II.
STRUCTURAL CHROMOSOME ABNORMALITIES

• Occur when chromosomes are broken by agents termed clastogens


• Unbalanced alterations: result in loss or gain of genetic material
• Balanced alterations: do not result in loss or gain of genetic material
• Can occur either in germline or somatic cells
• Translocations:
- Occur when chromosomes are broken and the broken elements
reattach to other chromosomes
- Two major types: reciprocal, Robertsonian
Reciprocal translocation
• Genetic material is exchanged between nonhomologous chromosomes
• A translocation carrier: often no clinical consequencies other than during
reproduction
When one parent is a reciprocal translocation
carrier:

• Adjacent segregation: produces unbalanced


genetic material and most likely loss of
pregnancy

• Alternate segregation: produces a normal


haploid gamete (and diploid conception) or
a liveborn who is a phenotypically normal
translocation carrier.
Reciprocal translocation after birth

• Occur by chance at the somatic cell level throughout life

• Often no consequence

• May alter the expression or structure of an oncogene or a tumor


supressor gene  abnormal growth advantage to the cell

• Ex: t(9;22) chronic myelogenous leukemia; t(15;17) acute


myeogenous leukemia; t(4;18) follicular lymphomas…
Robertsonian translocations
• Much more common, #1/1000 live births
• Occur only in acrocentric chromosomes (13, 14, 15, 21, 22)
• Loss of short arms of two of the chromosomes, subsequent fusion of the
long arms
• Ex: 45,XY,-14,-21,+t(14q;21q)
Deletions

• Occur when a chromosome loses


some of it genetic information

• May be caused by agents that cause


chromosome breaks and by
unequal crossover during meiosis

• Ex: Cri-du-chat syndrome


Microdeletions

Too small to be apparent


microscopically without
special flourescent probes
(FISH)
OTHER CHROMOSOME ABNORMALITIES

Inversions: chromosome segment between two


breaks is reinserted in the same location but in
reverse order

- usually unaffected
- homologous chromosomes must line up during
meiosis → inverted chromosomes will form loops
that, through recombination, may result in a
gamete that contains a deletion or a duplication,
which may then be transmitted to the offspring
Ring chromosome

• Can form when a deletion occurs on


both tips of a chromosome and the
remaining chromosome ends fuse
together
• Female with a ring X: 46,X,r(X)
• Are often lost, resulting in a monosomy
• Ex: loss of ring X chr. → Turner synd.
Isochromosome
• When a chromosome divides along the axis
perpendicular to its normal axis of division,
an isochromosome is created

• Autosomal isochromosome: usually lethal

• Karyotype of an isochromosome for the


long arm of chrX: 46,X,i(Xq) → Turner
syndrome
ADVANCES IN MOLECULAR CYTOGENETICS

Fluorescence in situ Hybridization (FISH)


A chromosome-specific DNA segment is labeled with a Fluorescent tag to
create a probe. This probe is then hybridized with the patient’s chromosomes,
which are visualized under a Fluorescence microscope.
• detects aneuploidies, translocations, and deletions (including
microdeletions) (mark the presence of the chromosome segment being
tested)
• do not have to be in the metaphase stage for accurate diagnosis.
Spectral Karyotyping
• involves the use of 5 different Fluorescent probes that hybridize differentially
to different sets of chromosomes.
• In combination with a special camera and image-processing software, this
technique produces a karyotype in which every chromosome is “painted” a
different color.
• This allows for the ready visualization of chromosome rearrangements such as
small translocations, e.g., the Philadelphia chromosome rearrangement t(9;22)
involved in chronic myelogenous leukemia.

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