1. Structural Chromosomal Abnormalities Mohamad Nusier M.D., Ph.D.

2. Structural chromosomal abnormalities
Translocations
Insertions
Inversions
Deletions
Ring formation
Isochromosomes
Extra Supernumerary Accessory Chromosome

3. Structural chromosomal abnormalities...cont
Translocations
2 different chromosomes break and rejoin incorrectly
Inversions
2 breaks in the same chromosome
Insertions
Piece of chromosomes inserted
Deletions
Piece of chromosome missing

4. Chromosomal Structural Changes
- Normal ----> ABCDEFG - Duplication ----> ABCBCDEFG - Deletion ----> AB_DEFG - Insertion ----> ABCXDEFG - Inversion ----> ACBDEFG - Translocation ----> AGFBCDE

5. Origins of chromosomal rearrangements

6. Types of Rearrangements In Term of consequences
Balanced: abnormalities do not change gene dosage (The number of copies of a given gene present in a cell or nucleus. An increase in gene dosage can result in the formation of higher levels of gene product)
Inversions.
Translocations.
 Imbalanced: abnormalities alter gene dosage causing aneuploidy (the presence of an abnormal number of chromosomes in a cell)
Deletions.
Duplications.

7. Translocations
Transfer of DNA segments from one chromosome to another.
Reciprocal:
Arise when two chromosomes break and exchange pieces; two new derivative chromosomes will form.
Involves any chromosome
Robertsonian:
Break points are at or close to centromeres of two acrocentric chromosomes
Chromosomes 13, 14, 15, 21, 22

8. Reciprocal Translocations
Incidence in population is 1 in 500
The most common type
Break in any chromosome at any point
Occur at meiosis
Phenotypically normal
Usually needs FISH to be identified.
*der: derivative

9. Reciprocal Translocation at Meiosis
Normally chromosomes pair to form bivalents.
Reciprocal translocation heterozygote form a cluster known as pachytene quadrivalent (cross-shape).
Homologous materials align.
Segregation in several different ways.

10. Segregation of Reciprocal Translocations
Independent homologous segregation during meiosis I can result in one of two types of segregation
Alternate segregation = Alternate chromosomes go to each gamete resulting in balanced gametes
Adjacent segregation = Adjacent chromosomes go to each gamete resulting in duplicated and deficient gametes

12. Robertsonian translocations
Often 14:21 joined 
Lose satellite
Reduce chromosome number by 1, but no loss
Phenotypically normal – problems at meiosis
Involved in evolution

13. Genome restructuring by translocations (Robertsonian)
Short arrows indicate breakpoints in one homolog of each of two pairs of acrocentric chromosomes. The resulting fusion of the breaks yields one short and one long metacentric chromosome.
Under appropriate conditions, the short metacentric chromosome may be lost. Thus, we see a conversion from two acrocentric pairs of chromosomes into one pair of metacentrics.

14. Formation of a 14q21q Robertsonian translocation in Down syndrome
Formation of a 14q21q Robertsonian translocation in Down syndrome. Cause in less than 5% of cases.

15. Formation of a 14q21q Robertsonian translocation in Down syndrome
Formation of a 14q21q Robertsonian translocation in Down syndrome. Cause in less than 5% of cases.

16. Inversions Reversal of segment of chromosome
If too small cannot detect by karyotype
Very rare in humans
Paracentric – within one chromosome arm
Pericentric - reversed segment includes centromere

17. Pericentric - includes centromere
Paracentric - not involving centromere

18. Insertions
Segment of one chromosome inserted into another

19. Duplication
Possible pairing configurations in heterozygotes of a standard chromosome and a side-by-side duplication. Duplicated segments may be (a) in tandem or (b) in reverse order.

20. Deletions Terminal - loss of end of chromosome
46,XY,del(10)(q26) missing long arm of 10
Interstitial – loss of segment from within chromosome
46,XY,del(10)(q24q26) missing segment of 10
All result in unbalanced karyotype
Partial monosomy
Serious clinical effect

21. Isochromosome Two copies of the same arm
Mirror image around centromere
Centromeres part in wrong plane
Two groups:
Replaces a normal chromosome
Results in monosomy for 1 chromosome
Arm and trisomy for the other arm

22. Ring Chromosome

23. Extra Supernumerary Accessory Chromosome
Abnormal chromosome in addition to 46
Small and difficult to identify
Sometimes called marker chromosomes
Difficult to work out effect on person
May be benign or cause serious mental handicap

25. Standard nomenclature for chromosome karyotypes
46,XY: normal male chromosome constitution 47,XX,+21: female with trisomy 21, Down’s syndrome 47,XY, +21[10]/46,XY[10]: Male who is a mosaic of trisomy 21 cells and normal cells (10 cells scored for each karyotype) 46,XY,del(4)(p14): Male with distal deletion of the short arm of chromosome 4 band designated 14 46,XX,dup(5)(p14p15.3): female with a duplication of the short arm of chromosome 5 from bands p14 to p15.3

26. Standard nomenclature for chromosome karyotypes
45,XY,der(13;14)(q10;q10): A male with a balanced Roberstonian translocation of chromosomes 13 and 14. Karyotype shows that one normal 13 and one normal 14 are missing and replaced with a derivative chromosome 46,XY,t(11;22)(q23;q22): A male with a balanced reciprocal translocation between chromosome 11 and 22. The breakpoints are at 11q23 and 22q22 46,XX,inv(3)(p21;q13): An inversion on chromosome 3 that extends from p21 to q13; because it includes the centromere, this is a pericentric inversion 46,X,r(X): A female with one normal X chromosome and one ring X chromosome 46,X,i(Xq): A female with one normal X chromosome and an isochromosome of the long arm of the X chromosome

27. Examples of Microdeletion Syndromes
Wolf-Hirschhorn Syndrome Del(4p)
Cri Du Chat Syndrome Del(5p)
William’s Syndrome Del(7)(q11.2)
Miller-Dieker Syndrome Del(17)(p )
Prader-Willi/Angelman syndrome Del(15)(q11-13)
DiGeorge Syndrome Del(22)(q11)
WAGR syndrome Del(11)(p13)

28. Del(4p)(Wolf-Hirschhorn Syndrome)

29. WHS Karyotype: Del(4p)

30. Del(5p) (Cri Du Chat Syndrome)
Incidence: 1/50,000 live births
A distinct, shrill, cat-like cry (secondary to hypoplastic larynx), Mental retardation
5-10% (parental translocation)

31. Del(5p) (Cri Du Chat Syndrome)

32. Williams Syndrome

33. Miller-Dieker Syndrome

34. Deletions found consistently in several different types of solid tumors in humans. Band numbers indicate recurrent breakpoints.

35. Philadelphia chromosome
The Philadelphia chromosome was first observed in 1960 and is found in 95% of cases of chronic myeloid leukaemias.
The Philadelphia chromosome is a reciprocal translocation of DNA between the long arms of chromosomes 22 and 9 - t(9;22).
The portion of 9q translocated contains abl, a proto-oncogene that is the cellular homolog of a tyrosine kinase coded by the Abelson murine leukaemia virus - ABL.

38. Translocations found consistently in several different types of solid tumors in humans. Band numbers indicate breakpoints.

39. Chromosome aberrations associated with representative solid tumors.
Meningioma: del(22)(q11)1
Neuroblastoma: del(1)(p36), del(11)(q23)
Renal cell carcinoma: del(3)(p14.2–p25) or translocation of this region
Retinoblastoma, osteosarcoma: del(13)(q14.1) or translocation of this region
Small-cell lung carcinoma: del(3)(p14–p23)
Wilms' tumor: del(11)(p15)

40. The Pseudoautosomal Regions
Genes located within them (so far only 29 have been found) are inherited as autosomal genes.
Males have two copies of these genes: one in the pseudoautosomal region of their Y, the other in the corresponding portion of their X chromosome.

41. SRY
A gene located on the short (p) arm just outside the pseudoautosomal region.
It is the master switch that triggers the events that converts the embryo into a male.
Without this gene, you get a female instead. It appears, then, the femaleness is the "default" program.

42. 46,XY female with deletion of SRY gene
During meiosis, the pseudoautosomal regions on the short arms of X and Y pair and undergo recombination
The SRY gene is located next to the Yp pseudoautosomal region, and if it is transferred to the X chromosome, a 46,XX male or 46,XY female would result

43. Indications for cytogenetic analysis
Patients of any age who are grossly retarded physically or mentally, especially if there are associated anomalies.
Any patient with ambiguous internal or external genitalia or suspected hermaphroditism.
Girls with primary amenorrhea and boys with delayed pubertal development. Up to 25% of patients with primary amenorrhea have a chromosomal abnormality.
Males with learning or behavioral disorders who are taller than expected (based on parental height).
Certain malignant and premalignant diseases.

44. Indications for cytogenetic analysis...cont
Parents of a patient with chromosome translocation.
Parents of a patient with a suspected chromosomal syndrome if there is a family history of similarly affected children.
Couples with a history of multiple spontaneous abortions of unknown cause.
Couples who are infertile after more common obstetric and urologic causes have been excluded.
Prenatal diagnosis.