Chromosomal Abnormalities I SDK October 21, 2013

1. Chromosomal Abnormalities ISDKOctober 21, 2013

3. Chromosomes • Chromosomes are tiny string-like structures in cells of the body that contain the genes • Each person normally has 23 pairs of chromosomes, or 46 in all. • We inherit one chromosome per pair from our mother and one from our father.

4. Chromosomal Abnormalities • However, When a baby is born with too many or too few chromosomes, or with one or more chromosomes that are missing a piece or are rearranged, is suffering from chromosomal abnormalities.

5. Chromosomal Abnormalities • About 1 in 150 babies is born with a chromosomal abnormality. • A change in the number or structure of chromosomes can cause problems with growth, development, and function of the body’s systems. • Children with a chromosomal abnormality have mental and/or physical birth defects. • 95% of chromosomally abnormal conceptus are aborted spontaneously • Abortion mostly occurs in 1st trimester

6. Chromosomal Abnormalities • The majority of human chromosomal abnormalities occur in the Autosomes.  • Most of these abnormalities are monosomies or trisomies.  • In the case of a monosomy, there is only one copy of each kind of chromosome instead of the usual pair of homologous chromosomes.  • With trisomy, there are three of each type of chromosome.  • All fetuses with autosomalmonosomies spontaneously abort early in pregnancy.  • Likewise, almost all fetuses with trisomies die before birth.  • Those that survive usually have multiple physical malformations, mental retardation, and relatively short lives.

7. Chromosomal Disorders • 50% of 1st trimester miscarriages(Before 24 week) • 5% of stillbirths(from 24 week to) • 0.5% of live borns • Down syndrome—trisomy 21 • Fragile X syndrome • Somatic cell abnormalities in cancers

8. Chromosomal Abnormalities What are chromosome abnormalities? A chromosome abnormality reflects an abnormality of chromosome number or structure. We can classify them into: I- NUMERICAL ABNORMALITIES II- STRUCTURAL ABNORMALITIES

9. I. NUMERICAL ABNORMALITIES

10. NUMERICAL ABNORMALITIESHOW DOES IT HAPPEN Chromosomal abnormalities in the number of chormosomes. • Euploidy • Aneuploidy

11. NUMERICAL ABNORMALITIESHOW DOES IT HAPPEN 1.Euploidy: Cells has chromosomes multiple of 23 such as • 23, 46. 69, and 92 • These may be normal or Abnormal • Normal • Haploid cells : Gametes has 1 copy each 23 cells • Diploid cells: Somatic cells has 2 copy each 23 x2= 46 Abnormal • Tripoloidy 3 copies of each chromosome 23 x 3= 69 • 1 egg fertilized by 2 sperms • Tetra ploidy. 4 copies of each chromosome 23 x 4= 69 • 1 egg fertilized by 3 sperms

12. 2.Aneuploidy • Deviation from normal number of chromosomes due to loss or gain of specific chromosomes. • Generally caused by “non-disjunction” of chromosome during meiosis. • It is a major cause of human reproductive failure. • Most human miscarriages are aneuploids. • All autosomal monosomies are lethel • Most of all Trisomiesare also lethel • But some Trisomies[ three copies of a particular chromosomes] are compatible with survival to term with chromosomes 13, 18, and 21.

13. Types of Aneuploidy The different conditions of aneuploidy are: • Nullisomy - the loss of both pairs of homologous chromosomes; individuals are called nullisomics and their chromosomal composition is 2N-2. Humans with this condition will not survive. • Monosomy - the loss of a single chromosome; individuals are called monosomics and their chromosomal composition is 2N-1 • Trisomy - the gain of an extra copy of a chromosome; individuals are called trisomics and their chromosomal composition is 2N+1 • Tetrasomic - the gain of an extra pair of homologous chromosomes; individuals are called tetrasomics and their chromosomal composition is 2N+2

14. Cause of Aneuploidy • The development of aneuploids may have arisen by a process called non-disjunction. • Non-disjunction occurs when paired chromosomes do not separate either during meiosis I or meiosis II. • The direct result of this event is that gametes develop that have too few or too many chromosomes. • If this occurs during meiosis I normal gametes are not developed, • If it occurs during meiosis II half of the gametes will be normal and the other half will be abnormal.

15. Meiosis(Normal)

16. Non Disjunction at Meiosis I

17. Non Disjunction at Meiosis II

18. Non Disjunction (Quick Review)

19. Autosomal Chromosome Problems

20. Down Syndrome (Trisomy 21) • First identified by Dr. John Langdon Down in 1866 • Trisomy 21 • Associated with increased maternal age • The result of an extra copy of chromosome 21. People with Down syndrome are 47, 21+.

22. Down Syndrome (Trisomy 21) • Down syndrome affects 1:700 children and alters the child's phenotype either moderately or severely: • Characteristic facial features, short stature; heart defects • Susceptibility to respiratory disease, shorter lifespan • Often sexually underdeveloped and sterile, usually some degree of mental retardation. • Down Syndrome is correlated with age of mother but can also be the result of nondisjunction of the father's chromosome 21 in 1% cases.

23. Clinical findings • Newborn – hypotonia , increased sleepiness , excess nuchal skin • Mental retardation • The average IQ of children with Down syndrome is around 50, compared to normal children with an IQ of 100. • Small stature • Craniofacial findings – brachycephaly ( flat occiput ) , epicanthic folds , upward slanting eyes , protruding tongue, low set ears , flat nose , low nasal bridge , high arched palate . • Short broad hands • Clinodactyly ( incurving ) little finger • ASD,VSD , PDA • Anal duodenal atresia • Happy & affectionate

24. Clinical Features

26. Patau syndrome(Trisomy 13) • Patau Sundrome, also known as Trisomy 13 and Trisomy D. • Is a chromosomal abnormality, a syndrome in which a patient had an additional chromosome 13 due to non-disjunction of chromosomes during meiosis. • Some are caused by Robertsonian Translocations. • The extra chromosome 13 disrupts the normal course of development, causing serious eye, brain, circulatory defects as well as cleft palate, heart and kidney defects. • . 1:5000 live births. Children rarely live more than a few months.

27. Clinical Features • Polydactyl • Cleft Palate • Cutis Aplasia(Congenital absence of skin). is a congenital focal absence of epidermis. • Kidney Failures

28. Patau syndrome(Trisomy 13)

29. Edwards Syndrome (Trisomy 18) • Edward’s Syndrome also kwnon as Trisomy 18 (T18) or Trisome E. • It is a genetic disorder caused by the presence of all of an extra 18th chromosome (Trisomy 18). • It is named after John H. Edwards, who first described the syndrome in 1960. • It is the second most common autosomal trisomy, after Down Syndrome, that carries to term. • Edward’s Syndrome occurs in around one in 6,000 live births and around 80 % of those affected are female. • Children with full Trisomy 18 generally do not live more than a few months

30. Edwards Syndrome (Trisomy 18)

31. Clinical Features • Almost every organ system affected • Upturned Nose • Kidney Malformations • Omphalocele. • An omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall. • Arthrogryposis • Arthrogryposis, is characterized by multiple joint contractures and can include muscle weakness and fibrosis. • Microcephaly • Underdeveloped Phalanges

33. DiGeorge syndrome(Monosomy 22)22q11.2 deletion syndrome • Congenital thymic aplasia, and thymic hypoplasia • Is a syndrome caused by the deletion of a small piece of chromosome 22. • The deletion occurs near the middle of the chromosome at a location designated q11.2 • Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems

34. DiGeorge syndrome

35. Precursor T cell differentiation defect • Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T regulatory (Treg) cells • B cells are present but T-dependent B cell responses are defective • Anti-viral and anti-fungal immunity impaired • Developmental defect in the 3rd and 4th pharyngeal pouch • Results in facial defect and congenital heart disease • Treated with thymic transplant • Autosomal dominant trait

36. Pallister-Killian Syndrome • Pallister-Killian Syndrome also known as Tetrasomy 12p Mosaicism or Pallister Mosaic Aneuplody Syndrome. • Is a genetic disorder occurring in humans. • Pallister-Killian occurs due to the presence of the anomalous extra isochromosome 12p, the short arm of the twelfth chromosome. • An isochromosome is a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm • This leads to the development of Tetrasomy 12p. Because not all cells have the extra isochromosome, Pallister-Killian is a mosaic condition. • TETRASOMY in the smaller arm of chromosome 12. • 2n+2 or 48 chromosomes

37. Clinical findings • Hypo/Hyper Pigmentation • Epilepsy • High Foreheads • Flat nose • Supernumerary Nipples • Psychomotor Retardation

38. IDIC 15 (Isodicentric 15) • Isodicentric 15, also called idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15). • Isodicentric chromosome 15 is the scientific name for a specific type of chromosome abnormality. • Individuals with isodicentric chromosome 15, or "idic(15)", have 47 chromosomes instead of the typical 46 chromosomes. • The extra chromosome is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. • Individuals with idic(15) have a total of four copies of this chromosome 15. • With extra genetic material in chromosome 15. • 47 chromosomes

39. IDIC 15 (Isodicentric 15)

40. Clinical Features • Epicanthal Folds in the Eye • Short Stature • Delayed Language Development • Seizures • Some are Mentally Retarded

41. Which of the following is an example of monosomy? • 46,XX • 47,XXX • 69,XYY • 45,X

42. Sex Chromosome(X Y) Abnormalities Male Sex Female Sex

43. X Chromosome

44. Y Chromosome

45. Sex Chromosome Abnormalities • The majority of known types of chromosomal abnormalities involve Sex chromosomes. • In frequency of occurrence, they are only slightly less common than autosomal abnormalities.  • However, they are usually much less severe in their effects.  • Sex chromosome abnormalities are gender specific. 

46. Male Sex 1. Klinefelter Syndrome • Klinefelter syndrome: males inherit one or more extra X chromosomes--their genotype is XXY.  • 1 in 660 live male births • They characteristically have relatively high-pitched voices, asexual to feminine body contours as well as breast enlargement, and comparatively little facial and body hair.  • They are sterile or nearly so, and their Testes and Prostat glands are small.  • As a result, they produce relatively small amounts of testosterone. • Higher risk of breast cancer, extragonadal germ cell tumor and autoimmune diseases • 47,XXY-90% cases • 15% cases are mosaics

47. Male Sex 1. Klinefelter Syndrome

48. Clinical features • Scarce beard • Pubic ,chin & axillary hair absent • Longer fingers and arms • Sterile • Delicate skin • Normal lifespan

49. 2. XYY Syndrome • XYY syndrome males inherit an extra Y chromosome, their genotype is XYY.  • As adults, these "super-males" are usually tall (above 6 feet) and generally appear and act normal.  • However, they produce high levels of testosterone.  • During adolescence, they often are slender, have severe facial acne, and are poorly coordinated.  • They are usually fertile and lead ordinary lives as adults. 

50. 2. XYY Syndrome