Sex Chromosomes and
Abnormalities
Sex chromosomes
At the cellular level the
sex of an individual is
determined genetically
by the sex chromosomes.
X and Y -> male
X and X -> female
Dosage Compensation
Human females inherit two copies of every gene on the X
chromosome, whereas males inherit only one
But for the hundreds of other genes on the X, are males at a
disadvantage in the amount of gene product their cells
produce?
The answer is no, because females have only a single active X
chromosome in each cell.
X inactivation
“Lyon Hypothesis”
• Mary Lyon ve Liane Russell (1961)
• In a given cell, which of a female's X chromosomes
becomes inactivated and converted into a Barr body is a
matter of chance.
• After inactivation has occurred, all the descendants of that
cell will have the same chromosome inactivated.
• Thus X-chromosome inactivation creates clones with
different effective gene content.
Barr Body
Normal male,
Turner
0
1
2
3
Normal female,
Klinefelter
Barr Body
Lyon Hypothesis
X-chromosome inactivation occurs early in
embryonic development.
Mechanism of X-chromosome
inactivation
• Inactivation of an X chromosome
requires a gene on that chromosome
called XIST.
• XIST encodes a large molecule of RNA
• XIST RNA accumulates along the X
chromosome containing the active XIST
gene and proceeds to inactivate all (or
almost all) of the hundreds of other
genes on that chromosome.
• Barr bodies are inactive X chromosomes
"painted" with XIST RNA.
İnaktif X kromozomu
Xist RNA
Genes on the Y chromosome
•Y chromosome first seen 1923
•Tips of Y chromosome are
pseudoautosomal regions PAR1 and
PAR2
•They make up 5% of the
chromosome
•Contain 63 pseudoautosomal genes
that cross over with the X
chromosome
Genes on the Y Chromosome
•Y chromosome has 2
pseudoautosomal regions
whose genes match genes on
the X chromosome
•And a large central region
that does not recombine with
the X chromosome
•This non-recombining region
makes up about 95% of the
chromosome
X and Y are not homologous
Cytogenetic Abnormalities of the Sex
Chromosomes
• Sex chromosome abnormalities, like
abnormalities of the autosomes, can be either
numerical or structural and can be present in
all cells or in mosaic form.
Cytogenetic Abnormalities of the Sex
Chromosomes
• X and Y chromosome aneuploidy is relatively
common, and sex chromosome abnormalities
are among the most common of all human
genetic disorders, with an overall incidence of
about 1 in 400 to 500 births.
• The phenotypes associated with these
chromosomal defects are, in general, less
severe than those associated with comparable
autosomal disorders.
Cytogenetic Abnormalities of the Sex
Chromosomes
• Structural abnormalities of the sex chromosomes
are less common; the defect most frequently
observed is an isochromosome of the long arm of
the X, i(Xq), seen in complete or mosaic form in at
least 15% of females with Turner syndrome.
• Mosaicism is more common for sex chromosome
abnormalities than for autosomal abnormalities,
and in some patients it is associated with
relatively mild expression of the associated
phenotype.
Klinefelter Syndrome (47,XXY)
• The phenotype of Klinefelter
syndrome, the first human sex
chromosome abnormality to
be reported
• The patients are tall and thin
and have relatively long legs.
• They appear physically normal
until puberty, when signs of
hypogonadism become
obvious.
Clinical Picture
– Undersized penis and testes
hypospadias, small phallus or
cryptorchidism,
– Infertile,
– Somewhat feminized physical
chracteristics
– If desired, the XXY boy can
increase male
secondary sex
characteristics (body hair,
reduced breast development,
increased
muscle
development) w/testosterone
treatment
– language delay, learning
disabilities, or behavioral
problems
• Puberty occurs at a normal age, but the testes remain small,
and secondary sexual characteristics remain underdeveloped.
• Gynecomastia is a feature of some patients; because of this,
the risk of breast cancer is 20 to 50 times that of 46,XY males.
• Klinefelter patients are almost always infertile because of the
failure of germ cell development, and patients are often
identified clinically for the first time because of infertility.
• The incidence is at least 1 in 1000 male live
births
Associated endocrine complications include
• diabetes mellitus,
• hypothyroidism, and
• hypoparathyrodism ...
Lupus erythematosus, Sjogren syndrome, and rheumatoid
arthritis, are more common
Patients have often;
a low serum testosterone level but
high serum follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) levels.
• About 15% of Klinefelter patients have mosaic
karyotypes. As a group, such mosaic patients have
variable phenotypes; some may have normal testicular
development. The most common mosaic karyotype is
46,XY/47,XXY.
• There are several variants of Klinefelter syndrome, with
karyotypes other than 47,XXY, including 48,XXYY,
48,XXXY, and 49,XXXXY.
• As a rule, the additional X chromosomes cause a
correspondingly more severe phenotype, with a
greater degree of dysmorphism, more defective sexual
development, and more severe mental impairment.
47,XYY Syndrome
• The 47,XYY chromosome constitution is not
associated with an obviously abnormal
phenotype, and males with this karyotype
cannot be distinguished from normal 46,XY
males by any marked physical or behavioral
features.
Trisomy X (47,XXX)
• Trisomy X females, although somewhat above
average in stature, are not abnormal
phenotypically.
• XXX females develop pubertal changes at an
appropriate age, and they are usually fertile
although with a somewhat increased risk of
chromosomally abnormal offspring.
• There is a significant deficit in performance on IQ
tests, and about 70% of the patients have some
learning problems.
Turner Syndrome (45,X and Variants)
• Turner syndrome is much less common than
other sex chromosome aneuploidies. The
incidence of the Turner syndrome phenotype
is approximately 1 in 4000 female live births,
although much higher numbers have been
reported in some surveys.
Turner Syndrome (45,X and Variants)
•
•
•
•
•
•
•
•
•
Turner syndrome can often be
identified at birth or before puberty
by their distinctive phenotypic
features
At birth, infants with this syndrome
often have edema of the dorsum of
the foot.
short stature,
gonadal dysgenesis (usually streak
gonads reflecting a failure of
ovarian maintenance)
characteristic unusual facies
webbed neck
low posterior hairline
broad chest with widely spaced
nipples
elevated frequency of renal and
cardiovascular anomalies.
Turner Syndrome (45,X and Variants)
• Lymphedema may be
• The diagnosis should
present in fetal life,
also be considered in
causing cystic hygroma
the teenage years for
(visible by
girls with primary or
ultrasonography), which
secondary amenorrhea,
is the cause of the neck
especially if they are of
webbing seen
short stature.
postnatally.
• The most frequent chromosome constitution
in Turner syndrome is 45,X (sometimes
written incorrectly as 45,XO), with no second
sex chromosome. However, about 50% of
cases have other karyotypes. About one
quarter of Turner syndrome cases involve
mosaic karyotypes, in which only a proportion
of cells are 45,X.
• The most common karyotypes and their
approximate relative prevalences are as
follows:
46,X,i(Xq) 15%
45,X/46,XX mosaics 15%
45,X/46,X,i(Xq) mosaics about 5%
45,X, other X abnormality about 5%
Other 45,X/? mosaics about 5%
The chromosome constitution is clinically
significant.
For example, patients with i(Xq) are similar to
classic 45,X patients,
whereas patients with a deletion of Xp have
short stature and congenital malformations,
and those with a deletion of Xq often have
only gonadal dysfunction.