1. Chromosomes II Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of Tehran University
Website: (English)
(Persian)

2. Trisomy 18, 47 Ch.

3. Trisomy 18, 47 Ch. incidence of about 1 in 3,000
There is a 3:1 preponderance of females to males
Thirty percent of affected newborns die within the first month
50% by two months
and 90% by one year.
severe mental retardation
microcephaly
overlapping fingers, and rocker bottom feet
Neurologically they are hypertonic
Other common malformations include congenital heart, kidney, .... abnormalities.

4. Trisomy 18, 47 Ch.

6. Trisomy 13 (XX/XY, 47 Ch) has an incidence of 1 in 5,000
Forty-four percent of affected newborns succumb in the first month of life
and 69% by six months
Only 18% of the babies born with trisomy 13 survive the first year
microcephaly
microophthalmia (small eyes)
cleft lip or cleft palate
polydactyly (extra fingers)
congenital heart defects
urogenital defects
brain malformations
severe mental retardation.

7. Turner Syndrome ( 45, X)
45, X

8. Turner Syndrome (45, X)

9. Turner syndrome Only females One X chromosome
Or has two X chromosomes but one is damaged
Short stature
Delayed growth of the skeleton
Sometimes heart abnormalities
Usually infertile due to ovarian failure
Diagnosis is by blood test (karyotype)
1 out of every 2,500 female live births worldwide
Short neck with a webbed appearance

10. Kleinefelter/47XXY

11. Klinefelter syndrome (47, XXY)
In boys and men
47 chromosomes with XXY sex chromosomes
XXY is one of the most common chromosomal abnormalities
1 in 500 male births
the most common genetic cause of male infertility
Often : undiagnosed : variation in clinical presentation
Small testes , insufficient production of testosterone , and infertility

12. Klinefelter syndrome (47, XXY)
Breast enlargement, lack of facial and body hair, a rounded body type , to be overweight , and be taller than their fathers and brothers
Learning and/or behavioral problems
Testosterone replacement corrects the symptoms of androgen deficiency

13. Kleinefelter
XXY

14. Fragile X Syndrome
1 in 3,600 males and 1 in 4,000 to 6,000 females with the full mutation worldwide
It is estimated that 1 in 250 females and 1 in 700 males are carriers of the premutation.
It is second only to Down Syndrome as a cause of mental retardation
Fragile X syndrome appears in children of all ethnic, racial and socio-economic backgrounds

15. Fragile X Syndrome
most common inherited form of familial mental retardation
(CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype
Clinical features vary depending on age and seX
Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype

16. Fragile X Syndrome

17. Fragile X Syndrome

18. Chromosome abnormalities
Abnormality of chromosome number or structure:
Numerical Abnormalities
Structural Abnormalities

19. Structural Abnormalities
Deletions: A portion of the chromosome is missing or deleted (>5 Mb).
Paraderwilli Syndrome (Ch 15)
Angleman Syndrome (Ch 15)
Imprinting effect

20. Deletion refers to the loss of a segment of a chromosome
DELETIONS
Deletion refers to the loss of a segment of a chromosome
This can be terminal (close to the end of the chromosome on the long arm or the short arm)
or it can be interstitial (within)
eg.DGS II

21. DELETIONS

22. Structural Abnormalities
Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material.
Oncogenes (c-onc, c-fos, c-myc)

23. DUPLICATIONS
refers to an extra chromosomal segment within the same homologous chromosome or an extra chromosomal segment on another nonhomologous chromosome.
Again, the clinical findings are highly variable depending upon the chromosomal segments involved.
Gene expantion:
in Huntington Disease/ Fragile X, ….

24. Structural Abnormalities
Translocations: When a portion of one chromosome is transferred to another chromosome.

25. There are two main types of translocations.
In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.

26. Reciprocal TRANSLOCATIONS
Translocation 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

27. TRANSLOCATIONS

28. Balanced reciprocal translocation

30. Structural Abnormalities
Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted.
eg Ch9 inv in Iran

31. involve only one chromosome
Inversions
involve only one chromosome
the intervening segment is rejoined in an inverted or opposite manner.
Since there is no loss nor gain of chromosomal material, inversion carriers are normal
Paracentric: does not include the centromere
pericentric:inverted segment contains the centromere
In meiosis, the normal chromosome and the inverted chromosome will form a loop to allow pairing of specific DNA sequences
that occur within the inversion loop result in gametes with both deletions and duplications
inversion carriers have a relatively low risk of having abnormal offspring.

32. Inversions

33. Meiosis in an individual heterozygous for a pericentric inversion

34. Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.

35. Ring

36. Oncology Chronic Myelogenous Leukemia (CML)
a clonal expansion of transformed hematopoietic progenitor cells:
Myeloid
Monocytic
Erythroid
Megakaryocytic
lymphoid lineages

37. Molecular level CML: characterized by the bcr-abl fusion gene
reciprocal translocation t(9;22)(q34;q11)
creating the Philadelphia (Ph) chromosome
survival time of patients : to 5 to 7 years

38. Hematology Bone marrow

39. Chronic myelogenous leukemia (CML)
15% to 20% of leukemias in adults incidence of 1 to 2 cases per 100,000 population

40. Chronic myelogenous leukemia
occurs more frequently in males than in females (ratio of 1.3 to 1)
Incidence: increases with age
the median age at presentation is between 45 and 55 years
which is an important consideration for the selection of therapeutic strategies
stem-cell transplantation
treatment with interferon-alfa (Intron A, Roferon-A)

42. The Philadelphia Chromosome
a reciprocal translocation between the long arms of chromosome 9 and chromosome 22
the large segment of the c-abl gene from chromosome 9q34
to the part of the bcr gene on chromosome 22q11 in a head-to-tail fashion
creating a hybrid bcr-abl gene that is transcribed into a chimeric bcr-abl mRNA

45. Detection of bcr-abl Cytogenetic analysis
Ph chromosome in 90% of patients with CML
Such analysis is tedious and time-consuming
allows the examination of only 20 to 25 metaphases per bone marrow sample
misses the 5% of patients who are Ph-negative but bcr-abl-positive
Despite these shortcomings, cytogenetic analysis is the gold standard in the diagnosis of CML.

46. FISH Fluorescence in situ hybridization
allows for the analysis of metaphase
Results of FISH studies are easily quantifiable

47. fluorescence in situ hybridization (FISH)

48. fluorescence in situ hybridization (FISH)

49. FISH
Bcr
Abl
Abl-Bcr

50. Abl-Bcr