Lecture 9 - Chromosomal Abnormalities

Ronnee Yashon
Michael Cummings
Chapter 6
Chromosomal Abnormalities
Lecture objectives
• To understand cytogenetics: Karyotypes
 To
understand that changes in chromosome
number or structure can cause genetic disorders
Euploid: Normal two copies of each chromosome
Homologous chromosomes
• One derived from the father and
one derived from the mother.
• A set of chromosomes that carry

genes controlling the same
characteristics
(Exception is X and Y
chromosomes)
Homologous Chromosomes
• Chromosomes come in homologous

pairs,
• thus genes come in pairs.

Chromosome terminology
Comparison Between Homologs and Sister
Chromatids
Same or Different?
Chromosome Parts
 Centromere
 p arm (short arm)
 q arm (long arm)
 Telomeres (shorten
with each cell division)
Telomeres
• A protective cap at the end of
the DNA
• Every time a cell divides, the
telomere gets shorter
• Cells stop dividing when
telomere is gone completely
Nobel prize
http://nobelprize.org/nobel_prizes/medicine/laureates/2009/illpres.html
Chromosome abnormality can be tested by
examining Karyotype
• Karyotype
– a display of an individual’s complete set of chromosomes
- A karyotype is a
useful diagnostic
tool because it can
be used to identify
abnormalities in a
fetus’s
chromosomes early
in development.
What happens when there are too many or too
few chromosomes?
Normal meiosis
Separation of
homologous
chromosomes
Separation of
sister chromatids
Problems in Meiosis
Separation of
homologous
chromosomes
Separation of
sister chromatids
or sperm or sperm
Problems in Meiosis
Separation of
homologous
chromosomes
Separation of
sister chromatids
or sperm or sperm
Nondisjunction
 Chromosomes fail to separate
 Results in gametes and zygote with an abnormal chromosome number
 Aneuploidy is variations in chromosome number that involve one or more

chromosomes
Why should you care about
meiosis?
• Can cause infertility
• 50% of miscarriages are

caused by mistakes in meiosis
• Mistakes in meiosis can also

result in Down syndrome and
other genetic disorders
Aneuploidy: an abnormal number of chromosomes
• Effects vary by chromosomal condition
• Many cause early miscarriages
• Leading cause of mental retardation
• Most aneuploidy from errors in meiosis

Chromosomal Variations
Monosomy: only one copy of a chromosome
Trisomy: three copies of one chromosome
Polyploidy: multiple sets of chromosomes

Effects of Changes in Chromosomes
•Vary by chromosome and type of variation
•Can cause birth defects or fetal death
•Monosomy of any autosome is fatal
•Only a few trisomies (autosome) result in live

births
Trisomy 21: Down Syndrome (47,+21)
 1/800 (changes with age of mother)

 Survival up to age 50
 Leading cause of childhood mental retardation and heart defects
 Wide, flat skulls; eyelid folds; large tongues; physical, mental, development
retardation
 Can live rich, productive lives
Trisomy 13: Patau Syndrome (47,+13)
• 1/15,000
• Survival: 1–2 months
• Facial, eye, finger, toe, brain, heart, and nervous system
malformations
Trisomy 18: Edwards Syndrome (47,+18)
• 1/11,000, 80% females

• Survival: 2–4 months
• Small, mental disabilities, clenched fists, heart, finger, and foot malformations
• Die from heart failure or pneumonia
Nondisjunction of Sex Chromosomes
Aneuploidy and Sex Chromosomes: More common than in autosomes
• XO – Turner syndrome
• XXY – Klinefelter syndrome
• XXX – Triple X
• Y – nonviable (dead)
Turner Syndrome (45, X)
• 1 in 10,000
females
• Survival to adulthood
• Female, short, wide-chested,

undeveloped ovaries,
possible narrowing of aorta
• Normal intelligence
• 95–99% of 45,X conceptions

die before birth
Klinefelter Syndrome (47,XXY)
 Survival to adulthood
 Male
 Features do not develop
until puberty, usually sterile,
can have learning disabilities
 Many are mosaics
 1/1,000 males
XYY or Jacobs Syndrome (47,XYY)
• Survival to adulthood
• Average height, thin, personality disorders, some

form of mental disabilities, and adolescent acne
• Some can have very mild symptoms
• 1/1,000 male births

Summary
• Individuals born lacking one of the sex chromosomes or with an
additional X or Y chromosome usually survive
• These individuals usually have physical and/or physiological

problems
Uniparental Disomy (UPD)
• Embryo receives 2
copies of the same
chromosome from
one parent and no
copies from the other
parent
Uniparental Disomy
(UPD)
• Two copies of chromosome 15 from
father: Prader-Willi syndrome
(PWS)
• Two copies of chromosome 15 from

mother: Angelman syndrome (AS)
Chromosomal Structural Abnormalities
• duplication,
• deletion,
• inversion,
• translocation
Structural Changes in Chromosomes
Inversion
Translocation
What is the leading risk factor for trisomy
(e,g. Down’s Syndrome)?
Maternal age
Unknown why, older eggs

increase risk of
nondisjunction
Eggs held in meiosis I from

birth to ovulation
Can We Identify Chromosomal
Abnormalities in a Fetus?
Identification of Chromosomal
Abnormalities
Three tests:
1. Amniocentesis (> 16 weeks)
o Collects amniotic fluid
o Fetal cells grown and karyotype produced
2. Chorionic villus sampling (CVS) (10–12 weeks)

o Rapidly dividing cells
o Karyotype within few days
3. Free fetal DNA

Aminocentesis
Removal of about
20 ml of amniotic
fluid containing
suspended cells
that were sloughed
off from the fetus
Biochemical analysis
of the amniotic fluid Centrifugation
after the fetal cells
are separated out
Fetal cells are
Analysis of fetal cells removed from
to determine sex the solution
Cells are
grown in an
incubator
Karyotype analysis
Amniocentesis Only Used in Certain Conditions
 Risks for miscarriage; typically only done under one of
following circumstances:
oMother > 35
oHistory of child with chromosomal abnormalities
oParent has abnormal chromosomes
oHistory of infertility or multiple miscarriages

Chorionic Ultrasound to
villi monitor procedure
Developing
placenta
Developing fetus Bladder
Uterus
Chorion
Catheter
Amniotic
cavity
Rectum
Chorionic Villus Sampling

Less Invasive Testing Methods Free fetal DNA (ffDNA)
in amniotic fluid
Amniotic fluid ffDNA from paternal
Placenta chromosomes
ffDNA from maternal

chromosomes
Ways to Evaluate Risks
 Genetic counselors are part of the
health care team
 Provide information of
oDiagnosis
oProgression
oManagement of disorder
oPossible treatments
oPossible risks and recurrence
oAdjustment
oAlternatives
Canada - Programs with Full
Accreditation
•McGill University, Montreal, Quebec, Canada
•University of Toronto, Toronto, Canada
•University of British Columbia, Vancouver,
Canada
Take Home Message
When Too Much Or Too Little Count

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Ronnee Yashon

• A set of chromosomes that carry

• Chromosomes come in homologous

• thus genes come in pairs.

 p arm (short arm)

 q arm (long arm)

 Results in gametes and zygote with an abnormal chromosome number

 Aneuploidy is variations in chromosome number that involve one or more

• 50% of miscarriages are

• Mistakes in meiosis can also

• Many cause early miscarriages

• Leading cause of mental retardation

• Most aneuploidy from errors in meiosis

Trisomy: three copies of one chromosome

Polyploidy: multiple sets of chromosomes

•Can cause birth defects or fetal death

•Monosomy of any autosome is fatal

•Only a few trisomies (autosome) result in live

 1/800 (changes with age of mother)

• 1/11,000, 80% females

• Female, short, wide-chested,

• 95–99% of 45,X conceptions

• Average height, thin, personality disorders, some

• Some can have very mild symptoms

• 1/1,000 male births

• These individuals usually have physical and/or physiological

• Two copies of chromosome 15 from

Unknown why, older eggs

Eggs held in meiosis I from

2. Chorionic villus sampling (CVS) (10–12 weeks)

3. Free fetal DNA

oHistory of child with chromosomal abnormalities

oParent has abnormal chromosomes

oHistory of infertility or multiple miscarriages

Developing fetus Bladder

Chorionic Villus Sampling

ffDNA from maternal

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