Chromosomal Abnormalities II SDK October 28, 2013

1. Chromosomal Abnormalities IISDKOctober 28, 2013

3. II- STRUCTURAL CHROMOSOMAL ABNORMALITIES

4. II- STRUCTURAL ABNORMALITIES • Theses are group of problems that is caused by the structural abnormalities of the chromosomes. • Structural abnormalities may be Balanced or unbalanced • Balanced. Where there is no loss or gain of chromosome material • Un Balanced. An `unbalanced’ abnormality means that an individual has more or less chromosomal material than usual.(Loss or gain of genetic materail) • Structural abnormalities may occure in Germ cell or Somatic cells. • Those that happen in germ line cause difficulties in egg or sperm development and normal development of a zygote. This can be transferred to next generations • Those happen in Somatic cells can cause Cancer but are not transferred to next generation.

5. Types of Structural Abnormalities • Translocation • Reciprocal transloations • Robertsonian Translocation • Deletion and microdeletion • Duplication • Inversion • Pericentric inversion • Paracentricinversio • Insertion • Ring chromosome • Isochromosome • Chromosomal breakage/Instability: (e.g. Fanconi anemia, Bloom syndrome)

6. Types of Structural Abnormalities

7. 1. Translocation • A fragment of a chromosome is moved ("trans-located") from one chromosome to another - joins a non-homologous chromosome. Translocation are of 2 types • Reciprocal translocations • Robertsonian translocations

8. a- Reciprocal translocations • In a reciprocal translocation, two non-homologous chromosomes break and exchange fragments. • Individuals carrying such abnormalities still have a balanced complement of chromosomes and generally have a normal phenotype that is no symptoms. • May have some symptoms and varying degrees of subnormal fertility if break occur in the area where some important genes are present.. • However most of the DNA are Junk DNA do not code for any thing only 5% DNA is functional Coding DNA. • However this person can be a carrier and can transfer problem to next generation.

11. From Balanced to unbalanced Translocation • An unaffected carrier(Parents) of a `balanced’ translocation may have two kinds of offspring's • Child may have the same `balanced’ chromosomal translocation in their cells as their parent. • Child may have an unbalanced chromosomal translocation in their cells as compare to their parent

14. Examples of Reciprocal Abnormalities • Reciprocal Translocation of Chromosome 9 and 22(Produces Philadelphia Chromosome). This is because that the break occurred at an important gene which is actually an oncogene called “abl” oncogene this leads to CML(Chronic Myeloid Leukemia) • Reciprocal Translocation between Chromosome 8 and 14 result in overproduction of “myc” oncogene this leads to Burkitts Lymphoma.

15. CML(Chronic Myeloid Leukemia) Philadelphia Chromosome • It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. • CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors take place.

16. Epidemiology • CML occurs in all age groups, but most commonly in the middle-aged and elderly. • Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. • CML represents about 15–20% of all cases of adult leukemia in Western populations. • The only well-described risk factor for CML is exposure to ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.

17. Genetic Link • CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. • This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania.

18. The Philadelphia chromosome: • T (9:22) translocation.The Ph chromosome is a shortened chromosome 22, which result from Reciprocal translocation between the long arms of chromosomes 9 & 22. • The result is a hybrid bcr-abl gene (fusion protein) with increased tyrosine Kinase actinity and resulting in leukemic transformation.

19. BCR-ABL Gene • This exchange brings together two genes: • The BCR (breakpoint cluster region) gene on chromosome 22 and the • Proto-oncogene ABL (ableson leukemia virus) on chromosome 9. • The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth.

20. The clinical manifestations of Chronic Myeloid Leukemia (CML) • The clinical manifestations of Chronic Myeloid Leukemia (CML) are insidious and are often discovered incidentally when an elevated White Blood Cells (WBC) count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination. • Prognosis: Patient usually die within 6 months -- 2 years but may live for 5 years or more

21. CML(Chronic Myeloid Leukemia) Philadelphia Chromosome • AGE: CML is a disease of young adults ( ) 20 - 45 years, but may occur at any age. • Onset: Gradual. • Course : Spontenous remissions and exacerbations. The disease generally terminates in marrow transformation (AML) or failure associated with fibrosis. • Prognosis Patient usually die within 6 months --> 2 years but may live for 5 years or more.

22. Ultimate diagnosis of CML • Ultimately, CML is diagnosed by detecting the Philadelphia chromosome. • By routine cytogenetics, • By fluorescent in situ hybridization, or by • PCR for the bcr-abl fusion gene

23. Treatment • Chronic phase CML is treated with inhibitors of tyrosine kinase • Bone marrow transplantation • Stem cell transplantation

24. Burkitt’s Lymphoma • Burkitt's lymphoma (BL) is a tumor which was first described in 1958 by Denis Burkitt, a surgeon working in Africa. • It is a solid tumor of B Lymphocytes which form part of the white cell population in the blood and lymph glands. • It is one form of non-Hodgkin's lymphoma. The type of cell affected in Burkitt's lymphoma is the B lymphocyte which is normally involved in fighting infection by producing antibodies.

25. Burkitt’s Lymphoma * In most (approximately 90%) of the cases of Burkitt's lymphoma, a reciprocal translocation has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancers of the antibody heavy chain genes on chromosome 14.

26. Burkitt’s Lymphoma * Here is an actual karyotype of a cell from the tumor of a patient with Burkitt's lymphoma. The long (q) arm of the resulting chromosome 8 is shorter (8q-) than its normal homologue; the long arm of translocated chromosome 14 longer (14q+).

27. b- Robertsonian translocations • In Robertsonian translocations two different non homologous chromosome get stuck together. • This only occur between two acrocentric chromosomes. Robertsonian translocations (centric fusion)is a translocation in which the centromeres of two acrocentric chromosomes fuse to generate one large metacentric chromosome. • The karyotype of an individual carrying a centric fusion has one less than the normal diploid number of chromosomes.

28. Robertsonian translocations

32. Down Syndrome • Traditional type(95%) that is trisomy 21 an extra 21 chromosome due to non disjunction. • Robertsonian Translocation Trisomy 21(5%). that is an extra q arm of chromosome 21 on chromosome 14. • These translocational Down’s cases are heritable: several children in the same family can have the disease. • The translocation joins the long arms together on one centromere and the short arms is usually lost. The individual thus has a normal chromosome 14, a normal chromosome 21, and a translocation chromosome, called t(14;21).

33. Down Syndrome • In this case one of the parent may have Robertsonian Translocation and this is the cause of repeated abortions and miscarriage(Pregnancy loss). • So a female with a down child and repeated abortions might have Robertsonian Translocation .

34. 400 300 200 100 0 10 20 30 40 50 Incidence of Down Syndrome Increases with Maternal Age Number per 1000 Births Age of Mother (years)

35. 2. Deletion • A portion of one chromosome is lost during cell division. • That chromosome is now missing certain genes. • When this chromosome is passed on to offspring the result is usually lethal due to missing genes.

37. Terminal Deletion/ Cri Du Chat • Cri Du Chat: A specific Terminal deletion of a small portion of “chromosome 5” • These children have severe mental retardation, a small head with unusual facial features, and a cry that sounds like a distressed cat.

38. Aniridia-Wilms Tumor Syndrome • WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), • Aniridia (absence of the coloured part of the eye, the iris), • Genitourinary anomalies, and mental Retardation. • The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumours of the gonads (testes or ovaries). • The condition results from a deletion on chromosome 11 resulting in the loss of several genes

39. Aniridia-Wilms Tumor Syndrome • 1 in 50,000,000 births46 chromosomes.XY or XX • 11 Deletion of upper arm • Symptoms: • Mentally retarded • Growth retarded • Blindness • Tumors on kidneys • Short lifespan

40. Eighteen Q Deletion Syndrome • Distal 18q- is a genetic condition caused by a deletion of genetic material within one of the two copies of chromosome 18. • The deletion involves the distal section of 18q and typically extends to the tip of the long arm of chromosome 18. • 1 in 10,000,000 births • #18 Deletion of lower arm

41. Eighteen Q Deletion Syndrome • Mentally retarded • Heart disease • Abnormal hands and feet • Large eyes • Large ears • Normal lifespan

42. Eighteen Q Deletion Syndrome

43. Wolf- Hirschhorn Syndrome

44. Interstitial Deletion • Prader-Willi and Angelman Syndrome • Deletion at chromosome 15.

45. Angelman, Prader-Willi syndromes • Usually caused by large (megabase+) interstitial deletions of 15q11-q13 • Delete maternal chromosome = AS • Delete paternal chromosome = PWS

47. Symptoms of Angelman Syndrome • Developmental delay • Functionally severe Speech impairment • Movement or balance disorder • Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements • Short attention span

48. What is Prader-Willi Syndrome • Prader-Willi syndrome is caused by the absence of normally active genetic material on the long arm of chromosome 15. • Deletion on the paternal chromosome 15 • Prevalence: 1:12,000- 15,000 (both sexes, all races)

49. Symptoms of Prader-Willi Syndrome • Poor weight gain in infancy • Excessive or rapid weight gain between 1 and 6 • Delayed sexual maturity • Mild to moderate mental retardation • Obsession with food

50. Williams Syndrome • Autosomal dominant disorder • Occurs in approximately one of every 20,000 births