Chromosomes and Chromosomal Abnormalities Flashcards Preview

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Flashcards in Chromosomes and Chromosomal Abnormalities Deck (96):
1

3 types of Chromosomal structure

1) Metacentric

2) Submetacentric (p and q subunits)

3) Acrocentric (entirely below central line)

2

3 types of Chromosomal structure

1) Metacentric

2) Submetacentric (p and q subunits)

3) Acrocentric (entirely below central line)

3

Metaphase chromosomal structure

Stains show compaction

*there are different bands/stains per stage (ie: prophase has a lot)

4

Giemsa stain

Imaging chromosomal banding pattern

5

Dark bands

gene poor
heterochromatin

6

Light bands

gene rich- 50+ genes per band
euchromatin

7

How do you profile chromosomes?

1) Size
2) Centromere position
3) Banding pattern

8

When is profiling chromosomes necessary?

1) Problems in early growth and development
2) Stillbirth and neonatal death
3) Infertility
4) Family History
5) Neoplasia
6) Pregnancy for mother of advanced maternal age

9

Tissue sources for profiling chromosomes

Blood (somatic cells)
Cheek Cells (somatic cells)

Amniocentesis or CVS (prenatal screening)

10

Chromosomal analysis- duration?

Grow cells and stain DNA
Few days in between taking sample and getting diagnostic

11

Polyploidy

Polyploid cells and organisms are those containing more than two paired (homologous) sets of chromosomes

12

Aneuploidy

presence of an abnormal number of chromosomes in a cell, for example when having 45 or 47 chromosomes when 46 is expected in a human cell.

13

Ploidy

the number of sets of chromosomes in a cell, or in the cells of an organism.

14

Euploidy

Euploidy is the state of a cell or organism having the same number of each homologous chromosome

15

Consequences of meiotic nondisjunction

trisomy and monosomy

16

Origins of nondisjunction

associated more with oocytes than spermatocytes
can be traces back to meiosis

17

Nondisjunction and maternal age

rate of nondisjunction pretty steady up until 34-35 with rise increase after that

18

ACOG

practice guideline on prenatal aneuploidy screening and maternal age

maternal age independent- b/c improved low risk/noninvasive screening methods

19

ACMG

Recommended for trisomy 13, 18, 21
can be offered for sex chromosome aneuploidy and possibly clinically relevant deletions

complications:
maternal weight
maternal aneuploidy
organ transplant
gestational stage

20

Chromosomes with viable aneuploidy

13, 18, 21, X, Y

21

Where do most nondisjunction events trace back to?

Meiosis 1 in mothe

22

Which nondisjunction event potentially results in the least clinically severe outcome for resulting conceptions or fetuses?

post-zygotic mitosis

23

Difference between triploid and trisomy?

triploid- 3N

trisomy- 2N + 1

24

Mitotic- post zygotic- nondisjunction

Results in number of normal cells and few trisomic and monosomic cells

The monosomic cells have a hard time surviving so die out

The trisomic (aneuploid) cells only 25% of total cell volume and thus less severe

Phenotype also depends on which cells have the trisomy

25

FISH

hybridization using a probe with a complimentary sequence to chromosome you care about

easier to do after baby is born

26

Microarrays

each spot represents a unique part of the genome
normal reference- green
fetal- red

isolate DNA from each sample
label DNA with fluorescent tags

Mix samples and hybridize to the microarray

Rinse away unbound material; scan with a laser microscope

~comparing relative quantities
~this lets you scan the entire genome at once and look for changes in copy number

27

What can a karyotype do?

> 7-10 million bp

Detects copy number variation and positioning

28

What can a microarray do?

29

Trisomy 18

Edwards syndrome

clench fist
rocker bottom left foot
low set, malformed ears
mental retardation and cardiac malformations

only 5% survive birth, only 10% of those live past 2 years

30

Trisomy 13

Patau Syndrome

Bilateral cleft lip
Polydactyl
midline defects
heart, nervous system, growth malformations

31

Trisomy 21

Downs Syndrome
1 in 800

Hypotonia- low muscle tone
Short stature
open mouth with large tongue
Leukemia risk/ AD early onset

32

Robertsonian Translocation

46, XY, t(14;21), +21
46, XY, -14, t(14;21)

-as long as you have 2 copies of each you can by asymptomatic but at risk of passing it to child

33

Form of trisomy 21 with the highest risk of reoccurrence in subsequent pregnancy?

Robertsonian Trisomy 21

34

Dosage compensation

Males only have 1 X chromosome and females have 2....body tried to make it so that the double X acts like a single X --> leads to x inactivation in mammals

35

X inactivation

Doesn't matter how many X always shutting it down
so if female has 3 X, 2 are shut down
if make has 2 X, 1 is shut down

36

Escape from X inactivation

some genes that are still expressed in an inactivated X chromosome (mainly a part of the p section of the chromosome)

clincal phenotype is generally milder

37

Monosomy X

Turner Syndrome

Diagnosis at birth or puberty
Webbed neck
Short stature
lymph edema
amenhorrea- absence of period
infertility
normal intelligence

38

Trisomy XXY

Klinefelter Syndrome

2nd X goes thru X-inactivation but still some phenotype is expressed

Infertility
Hypogonadism
Gynecomastia- male breasts
Behavioral difficulties: learning, social, IQ

39

Paracentric inversions

pArA: an inversion that is away from centromere

*Inversions usually do not cause any abnormalities in carriers as long as the rearrangement is balanced with no extra or missing DNA

40

Pericentric Inversions

perI- inversion includes chromosome

41

Consequences of an inversion

Paracentric: Unbalanced offspring and genome instability
^chromosome has 2 centromeres and if spindle tries attaching at 2 spots, can rip the chromosome

Pericentric: Unbalanced offspring

42

Spectral Karyotyping (SKY)

Individual probe sets labelled in 24 different colors for each unique chromosome

Makes it easier to determine origin of any extra DNA

Especially useful to look for translocations..normal abnormalities would be obvious in normal G-banded karyotype

only use if expect substantial changes in # and structure

43

Reciprocal translocation

2 parts are swapped--> balanced translocation (# is still the same)

vast number are not going to create a fusion protein --> worry is at meiosis how will they be passed on

44

Chronic Myelogenous Leukemia

ie of reciprocal translocation

the t(9;22) gene acts like a kinase at the wrong times and places --> causes leukemia

46,XX, t(9;22)(q34;q11)

45

Principles of X inactivation

1) normally choice of Xi is random
2) choice may become non-random if one of the X chromosomes is severely defected in some way

46

What happens if one X chromosome is defective?

1) try to preserve the activity of one X equivalent
2) (if possible) preserve autosomal sequences

47

Unbalanced rearrangement

isochromosome- either 2 p arms or 2 q arms on the same chromosome thru deletion --> crossing over --> ring

48

Unbalanced rearrangement - Turner's Syndrome

45, XO = 46, XX, i(Xq)

49

5p15 deletion

Cri du chat

cry that sounds like a cat
mental retardation
microcephaly- abnormal head

50

Metaphase chromosomal structure

Stains show compaction

*there are different bands/stains per stage (ie: prophase has a lot)

51

Giemsa stain

Imaging chromosomal banding pattern

52

Dark bands

gene poor
heterochromatin

53

Light bands

gene rich- 50+ genes per band
euchromatin

54

How do you profile chromosomes?

1) Size
2) Centromere position
3) Banding pattern

55

When is profiling chromosomes necessary?

1) Problems in early growth and development
2) Stillbirth and neonatal death
3) Infertility
4) Family History
5) Neoplasia
6) Pregnancy for mother of advanced maternal age

56

Tissue sources for profiling chromosomes

Blood (somatic cells)
Cheek Cells (somatic cells)

Amniocentesis or CVS (prenatal screening)

57

Chromosomal analysis- duration?

Grow cells and stain DNA
Few days in between taking sample and getting diagnostic

58

Polyploidy

Polyploid cells and organisms are those containing more than two paired (homologous) sets of chromosomes

59

Aneuploidy

presence of an abnormal number of chromosomes in a cell, for example when having 45 or 47 chromosomes when 46 is expected in a human cell.

60

Ploidy

the number of sets of chromosomes in a cell, or in the cells of an organism.

61

Euploidy

Euploidy is the state of a cell or organism having the same number of each homologous chromosome

62

Consequences of meiotic nondisjunction

trisomy and monosomy

63

Origins of nondisjunction

associated more with oocytes than spermatocytes
can be traces back to meiosis

64

Nondisjunction and maternal age

rate of nondisjunction pretty steady up until 34-35 with rise increase after that

65

ACOG

practice guideline on prenatal aneuploidy screening and maternal age

maternal age independent- b/c improved low risk/noninvasive screening methods

66

ACMG

Recommended for trisomy 13, 18, 21
can be offered for sex chromosome aneuploidy and possibly clinically relevant deletions

complications:
maternal weight
maternal aneuploidy
organ transplant
gestational stage

67

Chromosomes with viable aneuploidy

13, 18, 21, X, Y

68

Where do most nondisjunction events trace back to?

Meiosis 1 in mother

69

Which nondisjunction event potentially results in the least clinically severe outcome for resulting conceptions or fetuses?

post-zygotic mitosis

70

Difference between triploid and trisomy?

triploid- 3N

trisomy- 2N + 1

71

Mitotic- post zygotic- nondisjunction

Results in number of normal cells and few trisomic and monosomic cells

The monosomic cells have a hard time surviving so die out

The trisomic (aneuploid) cells only 25% of total cell volume and thus less severe

Phenotype also depends on which cells have the trisomy

72

FISH

hybridization using a probe with a complimentary sequence to chromosome you care about

easier to do after baby is born

73

Microarrays

each spot represents a unique part of the genome
normal reference- green
fetal- red

isolate DNA from each sample
label DNA with fluorescent tags

Mix samples and hybridize to the microarray

Rinse away unbound material; scan with a laser microscope

~comparing relative quantities
~this lets you scan the entire genome at once and look for changes in copy number

74

What can a karyotype do?

> 7-10 million bp

Detects copy number variation and positioning

75

What can a microarray do?

76

Trisomy 18

Edwards syndrome

clench fist
rocker bottom left foot
low set, malformed ears
mental retardation and cardiac malformations

only 5% survive birth, only 10% of those live past 2 years

77

Trisomy 13

Patau Syndrome

Bilateral cleft lip
Polydactyl
midline defects
heart, nervous system, growth malformations

78

Trisomy 21

Downs Syndrome
1 in 800

Hypotonia- low muscle tone
Short stature
open mouth with large tongue
Leukemia risk/ AD early onset

79

Robertsonian Translocation

46, XY, t(14;21), +21
46, XY, -14, t(14;21)

-as long as you have 2 copies of each you can by asymptomatic but at risk of passing it to child

80

Form of trisomy 21 with the highest risk of reoccurrence in subsequent pregnancy?

Robertsonian Trisomy 21

81

Dosage compensation

Males only have 1 X chromosome and females have 2....body tried to make it so that the double X acts like a single X --> leads to x inactivation in mammals

82

X inactivation

Doesn't matter how many X always shutting it down
so if female has 3 X, 2 are shut down
if make has 2 X, 1 is shut down

83

Escape from X inactivation

some genes that are still expressed in an inactivated X chromosome (mainly a part of the p section of the chromosome)

clincal phenotype is generally milder

84

Monosomy X

Turner Syndrome

Diagnosis at birth or puberty
Webbed neck
Short stature
lymph edema
amenhorrea- absence of period
infertility
normal intelligence

85

Trisomy XXY

Klinefelter Syndrome

2nd X goes thru X-inactivation but still some phenotype is expressed

Infertility
Hypogonadism
Gynecomastia- male breasts
Behavioral difficulties: learning, social, IQ

86

Paracentric inversions

pArA: an inversion that is away from centromere

*Inversions usually do not cause any abnormalities in carriers as long as the rearrangement is balanced with no extra or missing DNA

87

Pericentric Inversions

perI- inversion includes chromosome

88

Consequences of an inversion

Paracentric: Unbalanced offspring and genome instability
^chromosome has 2 centromeres and if spindle tries attaching at 2 spots, can rip the chromosome

Pericentric: Unbalanced offspring

89

Spectral Karyotyping (SKY)

Individual probe sets labelled in 24 different colors for each unique chromosome

Makes it easier to determine origin of any extra DNA

Especially useful to look for translocations..normal abnormalities would be obvious in normal G-banded karyotype

only use if expect substantial changes in # and structure

90

Reciprocal translocation

2 parts are swapped--> balanced translocation (# is still the same)

vast number are not going to create a fusion protein --> worry is at meiosis how will they be passed on

91

Chronic Myelogenous Leukemia

ie of reciprocal translocation

the t(9;22) gene acts like a kinase at the wrong times and places --> causes leukemia

46,XX, t(9;22)(q34;q11)

92

Principles of X inactivation

1) normally choice of Xi is random
2) choice may become non-random if one of the X chromosomes is severely defected in some way

93

What happens if one X chromosome is defective?

1) try to preserve the activity of one X equivalent
2) (if possible) preserve autosomal sequences

94

Unbalanced rearrangement

isochromosome- either 2 p arms or 2 q arms on the same chromosome thru deletion --> crossing over --> ring

95

Unbalanced rearrangement - Turner's Syndrome

45, XO = 46, XX, i(Xq)

96

5p15 deletion

Cri du chat

cry that sounds like a cat
mental retardation
microcephaly- abnormal head