1. 1 ChromosomesI Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University Email: derakhshandeh@tums.ac.irderakhshandeh@tums.ac.ir Website: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984 (English)http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984 http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889 (Persian)

2. 2 What are chromosomes? Chromosomes are the structures that hold our genes Chromosomes are the structures that hold our genes genes Genes are the individual instructions that tell our bodies how to develop and function Genes are the individual instructions that tell our bodies how to develop and function They govern our physical and medical characteristics, such as hair color, blood type and susceptability to disease. They govern our physical and medical characteristics, such as hair color, blood type and susceptability to disease. Each chromosome has a p and q arm; p is the shorter arm and q is the longer arm. Each chromosome has a p and q arm; p is the shorter arm and q is the longer arm. The arms are separated by a pinched region known as the centromere The arms are separated by a pinched region known as the centromerecentromere

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4. 4 How many chromosomes do humans have? The typical number of chromosomes in a human cell is 46 - two pairs of 22 + XX/XY The typical number of chromosomes in a human cell is 46 - two pairs of 22 + XX/XY Holding an estimated 30,000 to 35,000 genes. Holding an estimated 30,000 to 35,000 genes. One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm). One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm).

5. 5 study of the chromosomes with a microscope, then Stainning with a microscope, then Stainning The chromosomes look like strings with light and dark "bands" The chromosomes look like strings with light and dark "bands" A picture, or chromosome map, of all 46 chromosomes is called a karyotype A picture, or chromosome map, of all 46 chromosomes is called a karyotypekaryotype The karyotype : identify chromosome abnormalities: that are evident in either the structure or the number of chromosomes. The karyotype : identify chromosome abnormalities: that are evident in either the structure or the number of chromosomes.

6. 6 study of the chromosomes The pairs have been numbered from 1 to 22, with the 23rd pair labeled "X" and "Y." The pairs have been numbered from 1 to 22, with the 23rd pair labeled "X" and "Y." In addition, each chromosome arm is defined further by numbering the bands that appear after staining In addition, each chromosome arm is defined further by numbering the bands that appear after staining The higher the number, the further that area is from the centromere. The higher the number, the further that area is from the centromere.

7. 7 Study of the chromosomes The first 22 pairs of chromosomes are called "autosomes" The first 22 pairs of chromosomes are called "autosomes"autosomes Final pair is called the "sex chromosomes." Final pair is called the "sex chromosomes."sex chromosomessex chromosomes The sex chromosomes an individual has determines that person's gender; females have two X chromosomes (XX), and males have an X and a Y chromosome (XY) The sex chromosomes an individual has determines that person's gender; females have two X chromosomes (XX), and males have an X and a Y chromosome (XY)

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9. 9 Karyotype 46 ), Xy)

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11. 11 How Chromosome Abnormalities Happen? MeiosisMitosis Maternal Age Environment

12. 12 Meiosis Chromosome abnormalities : Chromosome abnormalities : happen as a result of an error in cell division. happen as a result of an error in cell division. “Meiosis” : the cell division that the egg and sperm go through when they are developing. “Meiosis” : the cell division that the egg and sperm go through when they are developing. Normally, meiosis causes a halving of chromosome material, so that each parent gives 23 chromosomes to a pregnancy Normally, meiosis causes a halving of chromosome material, so that each parent gives 23 chromosomes to a pregnancy

13. 13 Meiosis

14. 14Meiosis

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16. 16 Chromosome abnormalities Abnormality of chromosome number or structure: Abnormality of chromosome number or structure: Numerical Abnormalities Numerical Abnormalities Structural Abnormalities Structural Abnormalities

17. 17 Numerical Abnormalities When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy). When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy).monosomytrisomymonosomytrisomy An example: Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). An example: Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of monosomy the individual is born with only one sex chromosome, an X. Turner Syndrome is an example of monosomy the individual is born with only one sex chromosome, an X. Kleinfelter Syndrome is an example of trisomy the individual is born with three sex chromosome, XXY. Kleinfelter Syndrome is an example of trisomy the individual is born with three sex chromosome, XXY.

18. 18 Down Syndrome (Trisomy 21( Trisomy 2(

19. 19 Down Syndrome (Trisomy 21(

20. 20 Down syndrom) Trisomy 21, 47) critical region: critical region: A region on the long (q) arm of chromosome 21 A region on the long (q) arm of chromosome 21 Down syndrome causes mental retardation, a characteristic facial appearance, and multiple malformations Down syndrome causes mental retardation, a characteristic facial appearance, and multiple malformations Associated with a major risk for heart malformations a small but still significant risk of acute leukemia. Associated with a major risk for heart malformations a small but still significant risk of acute leukemia. 3 copies of chromosome number 21 3 copies of chromosome number 21

21. 21 incidence of 1 in 660 and is by far the most common chromosomal abnormality incidence of 1 in 660 and is by far the most common chromosomal abnormality Slight flattening of the face Slight flattening of the face A low bridge of the nose (lower than the usually flat nasal bridge of the normal newborn) A low bridge of the nose (lower than the usually flat nasal bridge of the normal newborn) An epicanthal fold (a fold of skin over top of the inner corner of the eye, which can also be seen less frequently in normal babies) An epicanthal fold (a fold of skin over top of the inner corner of the eye, which can also be seen less frequently in normal babies) A ring of tiny harmless white spots around the iris A ring of tiny harmless white spots around the iris mental retardation mental retardation

22. 22 Down Syndrome: Prenatal Risk The risk of trisomy 21 is directly related to maternal age The risk of trisomy 21 is directly related to maternal age Patients who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis Patients who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis

23. 23 Women younger than 35 years should be offered maternal serum screening at 16 to 18 weeks of gestation Women younger than 35 years should be offered maternal serum screening at 16 to 18 weeks of gestation The maternal serum markers used to screen for trisomy 21 are alpha- fetoprotein, unconjugated estriol and human chorionic gonadotropin The maternal serum markers used to screen for trisomy 21 are alpha- fetoprotein, unconjugated estriol and human chorionic gonadotropin

24. 24 The use of ultrasound to estimate gestational age improves the sensitivity and specificity of maternal serum screening. The use of ultrasound to estimate gestational age improves the sensitivity and specificity of maternal serum screening.

25. 25 Etiology and Clinical Manifestations Trisomy 21 is present in 95 percent of persons with Down syndrome. Trisomy 21 is present in 95 percent of persons with Down syndrome. Mosaicism, a mixture of normal diploid and trisomy 21 cells, occurs in 2 percent. Mosaicism, a mixture of normal diploid and trisomy 21 cells, occurs in 2 percent.

26. 26 Etiology and Clinical Manifestations The remaining 3 percent have a Robertsonian translocation in which all or part of an extra chromosome 21 is fused with another chromosome. The remaining 3 percent have a Robertsonian translocation in which all or part of an extra chromosome 21 is fused with another chromosome.

27. 27 Robertsonian translocation The reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22 The reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22 On rare occasions, other non- acrocentric chromosomes undergo Robertsonian translocation On rare occasions, other non- acrocentric chromosomes undergo Robertsonian translocation

28. 28 Robertsonian translocation a reciprocal transfer of the whole long or short arms close to the centromere a reciprocal transfer of the whole long or short arms close to the centromere A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21 A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21 In meiosis, a trivalent is formed. In meiosis, a trivalent is formed.

29. 29 Robertsonian translocation

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32. 32 Frequency of Dysmorphic Signs in Neonates with Trisomy 21 Dysmorphic sign Frequency (%) Flat facial profile 90 Poor Moro reflex 85 Hypotonia 80 Hyperflexibility of large joints 80 Loose skin on back of neck 80

33. 33 Frequency of Dysmorphic Signs in Neonates with Trisomy 21 Dysmorphic sign Frequency (%) Dysmorphic pelvis on radiograph70 Small round ears 60 Hypoplasia of small finger60

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35. 35 Persons with Down syndrome usually have mild to moderate mental retardation Persons with Down syndrome usually have mild to moderate mental retardation School-aged children with Down syndrome often have difficulty with language, communication School-aged children with Down syndrome often have difficulty with language, communication Adults with Down syndrome have a high prevalence of early Alzheimer's disease Adults with Down syndrome have a high prevalence of early Alzheimer's disease

36. 36 Incidence of Some Associated Medical Complications in Persons with Down Syndrome Disorder Incidence (%) Mental retardation >95 Growth retardation >95 Early Alzheimer's disease 75% by age 60 by age 60 Congenital heart defect 40

37. 37 Disorder Incidence (%) Hearing loss 40 to 75 Ophthalmic disorders (congenital cataracts, glaucoma( 60 glaucoma( 60 Epilepsy 5 to 10 Gastrointestinal malformations )Hirschsprung disease) 5 Hypothyroidism 5 Leukemia 5

38. 38 Disorder Incidence (%) Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis(1-6 Infertility>99% in men anovulation in 30% of women

39. 39. Maternal Serum Screening FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.. FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.. FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8.FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8. Estimated risk of Down syndrome according to maternal age

40. 40 The risk of having a child with Down syndrome 1/1,300 for a 25-year-old woman; 1/1,300 for a 25-year-old woman; at age 35, the risk increases to 1/365 at age 35, the risk increases to 1/365 At age 45, the risk of a having a child with Down syndrome increases to 1/30 At age 45, the risk of a having a child with Down syndrome increases to 1/30

41. 41 Maternal Serum Screening If all pregnant women 35 years or older chose to have amniocentesis If all pregnant women 35 years or older chose to have amniocentesis about 30 percent of trisomy 21 pregnancies would be detected about 30 percent of trisomy 21 pregnancies would be detected Women younger than 35 years give birth to about 70 percent of infants with Down syndrome ! Women younger than 35 years give birth to about 70 percent of infants with Down syndrome !

42. 42 The risk of having a child with Down syndrome Maternal serum screening (multiple-marker screening) can allow the detection of trisomy 21 pregnancies in women in this younger age group. Maternal serum screening (multiple-marker screening) can allow the detection of trisomy 21 pregnancies in women in this younger age group.

43. 43 Maternal Serum Screening "triple test" or "triple screen" "Multiples of the Median (MoM)" Alpha-fetoprotein (AFP) Alpha-fetoprotein (AFP) unconjugated estriol unconjugated estriol human chorionic gonadotropin (hCG) human chorionic gonadotropin (hCG) the serum markers most widely used to screen for Down syndrome the serum markers most widely used to screen for Down syndrome

44. 44 "Multiples of the Median (MoM)“ & trisomy 21 With trisomy 21, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels With trisomy 21, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels maternal serum hCG is approximately two times higher than the normal hCG level maternal serum hCG is approximately two times higher than the normal hCG level

45. 45 Recurrence Risk and Family History If a patient has had a trisomy 21 pregnancy in the past, the risk of recurrence in a subsequent pregnancy increases to approximately 2-3 If a patient has had a trisomy 21 pregnancy in the past, the risk of recurrence in a subsequent pregnancy increases to approximately 2-3 percent above the baseline risk determined by maternal age percent above the baseline risk determined by maternal age

46. 46 Diagnosis of a chromosome-21 translocation in the fetus or newborn is an indication for karyotype analysis of both parents Diagnosis of a chromosome-21 translocation in the fetus or newborn is an indication for karyotype analysis of both parents If both parents have normal karyotypes, the recurrence risk is 2 to 3 percent If both parents have normal karyotypes, the recurrence risk is 2 to 3 percent

47. 47 Down Syndrome & Sampling Risks Methodrisk Chorionic villus sampling 10 to 12 weeks 0.5 to 1.5 % Early amniocentesis 12 to 15 weeks 1.0 to 2.0 % Second-trimester amniocentesis 15 to 20 weeks 0.5 to 1.0 %

48. 48 a woman having amniocentesis

49. 49 Counseling Aspects Women who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis. Women who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis. Women younger than 35 years should be offered maternal serum screening at 15 to 18 weeks' gestation. Women younger than 35 years should be offered maternal serum screening at 15 to 18 weeks' gestation.

50. 50 Ultrasound During the first trimester of the majority of pregnancies, it is possible to measure the size of the fluid area at the back of the fetus’s neck, known as the nuchal translucency or NT The increasing size of the NT indicates a greater risk of the fetus having Down’s syndrome. During the first trimester of the majority of pregnancies, it is possible to measure the size of the fluid area at the back of the fetus’s neck, known as the nuchal translucency or NT The increasing size of the NT indicates a greater risk of the fetus having Down’s syndrome.

51. 51Ultrasound

52. 52 Fluorescent In Situ Hybridisation techniques

53. 53 female fetus with trisomy-21 chromosomes 18 (aqua), X (green), and Y (red). chromosomes 18 (aqua), X (green), and Y (red). chromosomes 13 (green), and 21 (red) chromosomes 13 (green), and 21 (red)