chromosomal aberration of different chromosomal disorders

lecture of med 2

1. GENETIC
DISORDERS
PROF. DR. FLORENCIO C. DIZON
PATHOLOGY

3. DNA recombinant technology
Molecular basis of disease
Production of human biologically active agents
Gene therapy
Disease diagnosis

4. Structure of DNA
is double helix, with about 10
nucleotide pairs per helical
turn.
Each spiral strand, composed
of a sugar phosphate
backbone and bases
connected by hydrogen
bonding (non-covalent)
adenine (A) with thymine (T)
and guanine (G) with
cytosine (C).

5. Base Pair -A More Detailed Picture

6. The Genetic Code

7. Human Chromosomes
formed from a single DNA
molecule that contains many
genes.
a centromereattach the DNA
to the mitotic spindle.;
a telomerelocated at each end
of the linear chromosome

8. Chromosomes
hold our genes.
Genes are the individual instructions that
tell our bodies how to develop
there are 50,000 to 100,000 genes that are
located on 46 chromosomes.
These 46 chromosomes occur as 23 pairs.
The first 22 pairs are labelled longest to
shortest.
The last pair are called the sex
chromosomes labeled X or Y.

9. Chromosomes
Each chromosomes has a p and q arm
p (petit) is the short arm and q is
the long arm.
chromosomes like 13, 14, and 15
have very small p arms.
the q arm is always put on the
bottom and the p on the top. The
arms are separated by a region
known as the centromere, which is a
pinched area of the chromosome.

10. Karyotype
photograph of the
chromosomes from one
cell.
The cells analyzed are
usually white blood cells
chromosomes can be seen
as banded strings under
1,000 x magnification.
Cytogenetics the study of
chromosomes.

11. International Standard of
Cytogenetic Nomenclature.
method of describing chromosomes and
chromosome abnormalities.
some examples:
46,XX -Normal Female Karyotype
46,XY -Normal Male Karyotype
These descriptions say there are 46 chromosomes
and that it is a male or female.
46,XX,del(14)(q23)
Female with 46 chromosomes with a deletion of
chromosome 14 on the long arm (q) at band 23.

12. GENETIC DISORDERS
CYTOGENETIC DISORDERS
MENDELIAN DISORDERS
MULTIFACTORIAL INHERITANCE
SINGLE GENE DISORDERS

13. Cytogenetic disorder
Chromosomes mutation
Abnormal number or alterations in the structure
of one or more chromosomes
Euploid –exact multiple of haploid
Aneuploid –error occurs in meiosis a cell
acquire a complement that is not exact multiple
of 23

14. Mutation of Chromosomes
A permanent structural
alteration in DNA. In
most cases, such DNA
changes either have no
effect or cause harm,
but occasionally a
mutation can improve
an organism's chance
of surviving and
passing the beneficial
change on to its
descendants.

15. Mutation
Permanent change in DNA
Change in number of chromosomes
Genome mutations
Change in the stuctures of chromosomes
Chromosome mutations
Gene mutations

16. Gene Mutation
Complete or partial deletion of gene affecting
one gene
Point mutation
Insertion or deletion of one or two base pairs –
frameshift mutation

17. Chromosomes deletion
when a part of a chromosome(s) has
been deleted.
A deletion can occur on any
chromosome, at any band, and can
be any size (large or small).
What a deletion causes depends on
how big a piece is missing and what
genes are missing in the section

18. Deletion
loss of a segment of a
chromosome.
This can be terminal,
or it can be interstitial
(within the long arm or
the short arm).
cri-du-chat syndrome
(5p-). involve the loss
of the distal end of the
short arm.

19. Translocations
abnormalities which occur when
chromosomes break and the
fragments rejoin to other
chromosomes
the long arms of chromosome 7
and 21 have broken off and
switched places.
a normal 7 and 21, and a
translocated 7 and 21. This
individual has all the material
needed, just switched around
(translocated)

20. Abnormalities in Chromosome
Structure
Translocations
most clinically significant
involves two nonhomologous chromosomes (e.g.,
chromosome 2 and chromosome 6). Following a break
in each of the chromosomes, and subsequent reunion, a
segment of chromosome 2 becomes attached to
chromosome 6

21. Duplication
extra chromosomal
segment within the same
homologous
chromosome
an extra chromosomal
segment on another
nonhomologous
chromosome.

22. Causes of Chromosomal Disorders
ionizing radiation, autoimmunity, virus infections and
chemical toxins
Most cases of simple aneuploidy -monosomy or
trisomy -are likely due to meiotic non-
disjunctions.

23. Euploidy vs aneuploidy
Euploidy normal
number of structurally
normal chromosomes.
Euploid human females
have 46 chromosomes
(44 autosomes and two
X chromosomes).
Aneuploidy having less
than or more than the
normal diploid number
of chromosomes,
the most frequently
observed type of
cytogenetic
abnormality.

24. Aneuploidy is due to
nondisjunction
failure of normal separation of a
chromosome pair when the eggs
or sperm are formed during
meiosis.
The pairs of chromosomes are
separated (segregation) during
meiosis 1.
During meiosis 2, a second
division of the chromosomes
occurs resulting in the formation
of four sperm, or one egg and
three polar bodies, each with 23
chromosomes.
Nondisjunction can occur in
meiosis 1 or meiosis 2.

25. Monosomy vs Trisomy
Monosomy is lack of one of
a pair of chromosomes.
An individual having only one
chromosome 6 is said to have
monosomy 6.
A common monosomy seen in
many species is X
chromosome monosomy, also
known as Turner's syndrome.
Monosomy is most commonly
lethal during prenatal
development.
Trisomy is having three
chromosomes of a particular
type.
A common autosomaltrisomy in
humans inDown syndrome, or
trisomy 21, in which a person
has three instead of the normal
two chromosome 21s.
Trisomy is a specific instance
of polysomy, a more general
term that indicates having more
than two of any given
chromosome.

26. Chromosomal abnormalities
Most chromosomal abnormalities result in
spontaneous abortion.
As many as 50 60% of spontaneous abortions
are shown to have an underlying chromosomal
abnormality.
These abnormalities are numerical (aneuploidy)
or structural (rearrangement).

27. Cytogenetic disorder involving
autosomes
Down syndrome
Edwards syndrome
Patau syndrome

28. Down’s syndrome
Trisomy 21
Most common chromosomal disorder
Major cause of mental retardation
1/25 for mothers > 45
maternal age strong influence

29. Chromosome analysis reveals a 47, XY,
+21 karyotype typical for Down
syndrome.

30. Trisomy 21
-flat facial pofile
-epicanthal folds
-oblique palpebral fissures
-severe mental retardation
-congenital heart disease
-10 x acute leukemia
-> 21 y/o develop
Alzeimers disease
-abnormal immune
response

31. Edwards syndrome
The clenched fingers that
are overlapping are
typical for trisomy 18.
Micrognathia
Mental retardation
Low set ears
Congenital heart defects
Renal malformations

32. Patau syndrome
Midline defects, such as
the cleft lip shown here,
are typical (but not
specific)
Microphthalmia
Microcephaly
Umbilical hernia
Rocker bottom feet

33. Postaxial polydactyly, as
shown here, is quite
characteristic for trisomy
13.

34. Trisomy 13 has many
midline defects. Here is
cyclopia, with a single slit
for an eye (but no actual
eye present). A
protruding proboscis is
also seen.

35. Cytogenetic disorder involving
sex chromosomes
Klinefelters syndrome
Turners syndrome
Hermaphroditism.

36. Klinefelters syndrome
Male hypogonadism
47 XXY
Most frequent sex chromosome disorders
Increase length between soles and pubic bones
Small atrophic testes, Reduced spermatogenesis
Lack of secondary sex characteristics
FSH elevated

37. Klinefelter's syndrome
47, XXY karyotype. A
non-dysjunctional event
in meiosis (maternal or
paternal) left two X
chromosomes in an
ovum or a sperm.
Infertility results from
absent sperm.
About half have
gynecomastia.

38. Turners syndrome
Monosomy of X
Hypogonadism of phenotypic females
Edema
Swelling of the nape, cystic hygroma
Neck webbing
Coarctation of aorta
Streak ovaries

39. Turners syndrome
Fetal hydrops indicates a
poor prognosis, regardless of
the cause, and in about a
third of stillbirths, the cause
for hydrops is not found.
However, chromosomal
abnormalities should be
considered, and foremost
among them should be
Turner's syndrome.

40. Here is the 45, X
karyotype of monosomy
X (Turner's syndrome).

41. After puberty, the ovaries
should develop into
plump 3 to 5 cm ovoid
organs, but these
"streak" ovaries are
typical for Turner's
syndrome.

42. Thank you