Transcript Genetics: Getting Down to the Basics. Turner syndrome

Genetics:
Getting Down
to the Basics.
Turner
syndrome
Ginette Talbot, MSc, GCG
Genetic Counsellor
May 23, 2015
Overview
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Brief review of clinical features
Learning the language: chromosomes, genes
What are genes?
How does Turner syndrome happen?
X-inactivation: is it important?
Types of Turner syndrome
How to read a karyotype
Fun facts about the X chromosome
http://musom.marshall.edu/graphicdesign/ibooks/Genetics.html
Goodman RM, Gorlin RJ. The Malformed Infant and Child. Oxford University
Press. 1983.
What are genes?
 Genes
give instructions to the body to
make certain products, structures, etc.
 Eg. Hair colour, height, organs
 ~30,000 genes in our body
 Present in almost every cell
 Many genes need to work in pairs, but
some only need one functional copy
Another way to think about
genes…
 English
alphabet: A, B, C, D, E,…
 Example of English sentence:
A cat in the hat.
 DNA alphabet: C, G, A, T,…
 Example of DNA code:
CGATTATGTGCATTGCCCCAT…
Code for SHOX
gene
Another way to think about
DNA…
 Gene
working properly.
A cat in the hat.
A cat in the hat.
 Gene with half its function.
A cat in the hot.
A cat in the hat.
 Gene cannot give proper instructions.
A cat in the hot.
A cat in the hot.
With some genes on the X
chromosome
 Gene
working properly.
A cat in the hat.
A cat in the hat.
 Gene cannot function properly.
A cat in the hat.
But… not enough!
This is also called ‘haploinsufficiency’
How does Turner syndrome
happen?
 Remember
high school Biology?
 ‘Reproductive cycles of the cell’?
What are the chances of this
happening in another
pregnancy?
 Most
cases happen by chance;
recurrence risk is considered to be low.
 For women WITH Turner syndrome, the risk
of having children with Turner may be
increased depending of the individual
karyotype (for those who can conceive
naturally)
X-inactivation
Happens to all individuals with more than one
X chromosome
 Eg. 46,XX; 47,XXX; 47,XXY
 ONLY 1 X chromosome remains completely
active
 The other X chromosomes becomes
permanently inactive
*This makes sense if you think about males
having only one X chromosome
*Some genes stay active on both X
chromosomes (or X and Y in males)
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(1)
How is this important for Turner
syndrome?
 Some
genes stay activated on both
chromosomes
 If there is only one X chromosome, genes
cannot work in pairs properly
 This disruption of instructions leads to the
symptoms we see in Turner syndrome
Important genes on the X
chromosome
 SHOX:
bone development and growth
 Xp11: short stature; ovarian delvelopment
impaired in approx. 50 %
 Xq13, POF, BMP15: ovarian development
 Many genes have unknown function
‘Types’ of Turner syndrome
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Reminder: There is a lot of variability of
symptoms regardless of the type
‘Classic’: Typically individuals who are missing
one entire X chromosome
‘Partial’: Individuals with a part of the X
chromosome missing, or structural changes of
one X chromosome
‘Mosaic’: Individuals with two X chromosomes
in some cells, and others with only one X
chromosome
Examples
 45,
X
 45, X/46, XX
 45, X/46,X,r(X)
 45,X/46,X,del(Xp)
 45, XO
 46,X,dup(X)
Classic TS
Mosaic TS
Mosaic TS +
Structural variant
Structural variant TS
Relative Frequencies of Turner
Syndrome Karyotypes
Standard
monosomy
45,X
46 %
X mosaicism
X/XX, X/XXX
7%
Isochromosome
Xq
45,X/46,X,i(Xq)
46,X,i(Xq)
18 %
Ring
45,X/46,X,r(X)
16 %
Deletion Xp
45,X/46,X,del(Xp)
46,X,del(Xp)
5%
Structural
abnormality of Y
6%
Other
2%
Jacobs et al. (1997).
So… how DO you read a
karyotype? Sex chromosomes
Total # of chromosomes
So… how DO you read a
karyotype?
Sex chromosomes
Mosaicism
# of colonies
analyzed
Total # of chromosomes
Description of where
the structural change is
Abbreviation for structural
change
Eg. DUP > duplication
DEL > deletion
IDIC > isodicentric
r > ring
i > isochromosome
Structural changes
Structural changes (con’t)
Structural changes (con’t)
Structural changes (con’t)
Fun Facts About the X
Chromosome
X
chromosome represents about 5 % of
total DNA
 X chromosome likely has 800-900 genes
(~30,000 genes in the genome)
 75-80 % of cases, the single X
chromosome comes from the egg
 Males cannot survive without an X
chromosome (45,Y does not exist)
Thank-you!
Bibliography
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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th
edition. New York: Garland Science; 2002.
Gardner RJM, Sutherland GR. 3rd edition. Chromosome abnormalities
and genetic counseling. Oxford Univeristy Press. 2004.
Goodman RM, Gorlin RJ. The Malformed Infant and Child. Oxford
University Press. 1983.
Zhong Q, Layman LC. Genetic considerations in the patient with Turner
syndrome--45,X with or without mosaicism. Fertil Steril. 2012 Oct;98(4):7759.