1. Chromosomes Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University

2. What are chromosomes? Chromosomes are the structures that hold our genes 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. 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

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

6. Study of the chromosomes • The first 22 pairs of chromosomes are called "autosomes" • Final pair is called the "sex 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)

8. Karyotype 46), Xy)

10. How Chromosome Abnormalities Happen? Meiosis Mitosis Maternal Age Environment

11. Meiosis

12. Meiosis

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

15. Numerical Abnormalities • When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy). • 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. • Kleinfelter Syndrome is an example of trisomy the individual is born with three sex chromosome, XXY.

16. Trisomy 18, 47 Ch.

17. 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.

18. Trisomy 18, 47 Ch.

20. 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.

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

22. Turner Syndrome (45, X)

23. 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

24. Kleinefelter XXY

25. Kleinefelter/47XXY

26. 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

27. 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

28. 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

29. 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

30. Fragile X Syndrome

31. Fragile X Syndrome

32. Down Syndrome(Trisomy 21(Trisomy 13 & 18

33. Down Syndrome (Trisomy 21( Trisomy 2(

34. Down Syndrome (Trisomy 21(

35. Down syndrom) Trisomy 21, 46) • critical region: • A region on the long (q) arm of chromosome 21 • Down syndrome causes mental retardation, a characteristic facial appearance, and multiple malformations • Associated with a major risk for heart malformationsa small but still significant risk of acute leukemia . • 3 copies of chromosome number 21

36. incidence of 1 in 660 and is by far the most common chromosomal abnormality • Slight flattening of the face • 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) • A ring of tiny harmlesswhite spots around the iris • mental retardation

37. Down Syndrome

38. Down Syndrome: Prenatal Risk • 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

39. The use of ultrasound to estimate gestational age improves the sensitivity and specificity of maternal serum screening. (Am Fam Physician 2000;62:825-32,837-8.)

40. Etiology and Clinical Manifestations • 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.

41. 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.

42. Robertsonian translocation • 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

43. Robertsonian translocation • 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 • In meiosis, a trivalent is formed.

44. Frequency of Dysmorphic Signs in Neonates with Trisomy 21 Dysmorphic signFrequency (%) Flat facial profile90 Poor Moro reflex85 Hypotonia80 Hyperflexibility of large joints80 Loose skin on back of neck 80 Slanted palpebral fissures80

45. Frequency of Dysmorphic Signs in Neonates with Trisomy 21 Dysmorphic sign Frequency (%) Dysmorphic pelvis on radiograph 70 Small round ears60 Hypoplasia of small finger60

46. Persons with Down syndrome usually have mild to moderate mental retardation • 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

47. Adult Down Syndrome

48. Incidence of Some Associated Medical Complications in Persons with Down Syndrome DisorderIncidence (%) Mental retardation>95 Growth retardation>95 Early Alzheimer's disease 75% by age 60 Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect40

49. Disorder Incidence (%) Hearing loss 40 to 75 Ophthalmic disorders (congenital cataracts, glaucoma( 60 Epilepsy5 to 10 Gastrointestinal malformations (duodenal atresia, Hirschsprung disease)5 Hypothyroidism5 Leukemia5

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