SF 002 Cytogenetics

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SF 002 Cytogenetics

• R. Daniel Gietz Ph.D.

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Learning objectives

• Understand the terms associated with chromosomes
  and karyotype.
• Understand how to write the karyotype of an
  individual.
• List and explain the different types of problems
  associated with chormosome number that are found
  in the population.
• Understand how problems with aneuploidy can
  occur.
• List and describe the most common aneuploideis
  described.
• List and described the problems that can occur in
  chromosome structure and how they can affect
  phenotype.

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Cytogenetics

• The study of chromosomes and their abnormalities.
  
• Chromosome abnormalities are responsible for a
  significant portion of genetic disease in the
  population with a prevalence of approximately
  1/150 live births.

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Cytogenetic Nomenclature

Chromosome are visualized during metaphase when
they condense prior to mitotic division. There
are 22 pairs of autosomes in a human cell and I
pair of sex chromosomes.
Human male G banded chromsomes
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Human male Karyotype
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Chromosome Types
Chromosome banding. Chromosomes are stained with
various dyes enabling the chromosome segments to
be identified. Most methods can distinguish
between 300 and 450 bands. High resolution
methods can distinguish up to 800 bands that can
allow identification of small interstitial
deletions.
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Karyotype nomenclature
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Chromosome Banding
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Fluorescence In situ Hybridization and
Comparative Genomic hybridization
New technique that uses chromosome specific DNA
as a probe to hybrize to metaphase, prophase and
interphase chromosomes. Can be used to identify
deletions, as well as inversions and
translocations.
The spots represent a t(25)(p23q35)
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Sky Karyotyping
This technique allows each chromosome to be
identified individually using special hardware
and software.
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Sky Karyotyping Cancer Cells
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Problems with chromosome number
Normal human cell contains 23 chromosome pairs is
considered to euploid (Greek, eu good, ploid
set). Polyploidy is a rare condition and is
lethal in humans (69 and 92). Triploidy can
occur at 1/10,000 live births. Aneuploidy Monosomi
c, XO Turners syndrome Trisomic, Downs
syndrome Due to chromosome non-disjunction in
meiosis. I or II.
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Common Trisomies in humans

• Trisomy 21 or Down Syndrome
• 47, XY, 21 or 47, XX, 21 Karyotype
• 1866 first described by John Langdon Down. In
  1959 it was discovered that it was due to an
  extra chromosome 21.
• Numerous problems including, obstruction of
  duodenum, or atresia of the esophagus, duodenum
  or anus.
• 40 are born with structural heart defects.
  Atrioventricular canal Ventricular septal
  defects.
• 95 of all Down syndrome are due to
  non-disjunction, rest are translocation.
• 90 - 95 are maternally derived.
• 1 - 3 being mosaics.
• Region is 21 q22
• Genes such as DYRK kinase or the APP gene may be
  responsible for the phenotype

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Human Trisomy 21 XY male.
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Common Trisomies in humans

• Trisomy 18 Edward syndrome
• 47, XY, 18 Karyotype.
• Second most common trisomy in humans
• Prenatal growth deficiency, characteristic facial
  features and distinctive hand abnormality.
  Congentical heart defects similar to Down
  Syndrome.
• Significant mortality 10 of patient only live
  to 12 years of age.

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Common Trisomies in humans

• Trisomy 13
• 47, XY, 13 or Karyotype
• Patau syndrome 1/10,000 live births.
• Malformations are distinctive and usually permit
  clinical diagnosis.
• Oral facial clefts, microphthalmia, and post
  axial polydactyly.
• Survival rate is similar to Trisomy 18
• 80 have full trisomy, rest trisomy of the long
  arm due to a translocation.
• 95 of all Trisomy 13 are lost duing pregnancy.

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Maternal Age and non-disjunction

• Down syndrome is found 1/1000 in women under 30.
• 1/400 at the age of 35
• 1/100 at the age of 40
• 1/50 at the age of 45.
• Due to the female oocytes are produced duing
  embryonic development and remain in prophase I
  until they are shed.
• Mechanism not understood

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Common Trisomies in humans

• Sex Chromosome more common in males (1/400) than
  females
• Turners syndrome 1/2500 - 1/5000 XO
• Describe in 1938 by Henry Turner
• Short stature, sexual infantilism and ovarian
  dysgenesis
• 50 of cases have structural kidney defects.
• 30 to 40 are mosaics.
• 80are caused by non-disjunction in the father..
• Kleinfelter Syndrome XXY
• Described in 1942 by Harry Kleinfelter and occurs
  about 1/1000 live births
• Hypogonadism, tall stature and 1/3 show breast
  development.
• Have seen XXXY and XXXXY males but still male.

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Common Trisomies in humans

• Trisomy 47, XXX
• Usually found 1/1000 individuals..Suffer from
  infertility. Most cases are diagnosed at
  fertility clinics..
• 47 XYY syndrome.
• Males tend to be taller have a lower IQ.
• Found as high as 1/30 in prison populations
• 1/1000 in general population
• Not associated with violence but associated with
  hyperactivity, ADD and learning disabilities.

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Abnormalities in Chromsome structure

• Translocations
• 1/500 prevalence.
• Reciprocal translocations
• Robertsonian translations

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Reciprocal Translocation
http//www.tokyo-med.ac.jp/genet/cai-e.htm
Reciprocal Translocation
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Reciprocal Translocation
http//www.tokyo-med.ac.jp/genet/cai-e.htm
Trisomy and monosomy

-gt

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Robertsonian Translocation
http//www.tokyo-med.ac.jp/genet/cai-e.htm
Robertsonian Translocation
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Products of meiosis Can give both normal and
unbalanced Progeny.
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Deletions
Deletion syndrome. 46, XX, del5p
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Ring chromosomes
Ring X chromome.
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Inversions
http//www.tokyo-med.ac.jp/genet/cai-e.htm
Pericentri inversion
Paracentric Inversion
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Isochromosomes
Isochromosome
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Clinical Abnormalities and phenotypes
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Cancer Cytogenetics
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Other cytogenetic abnormalities in cancer