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MCG > LEC42: Inborn Errors of Development: Chromosomes and Cytogenetics > Flashcards

LEC42: Inborn Errors of Development: Chromosomes and Cytogenetics Flashcards

1
Q

cytogenetics?

A

study of chromosomes

mechanisms of chromosomal disorders (microscopic & submicroscopic)

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2
Q

what proportion of 1st trimester spontaneous abortions do chromosome abnormalities cause?

A

2/3

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3
Q

what % of cardiac defects do chromosome abnormalities cause?

A

20% of pts w/ cardiac defects

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4
Q

what % of individuals w/ intellectual disability have a chromosomal abnormality?

individiuals w/ autism and cardiac defects?

A

intellectual disability: 20-30%

autism, cardiac defects: 20% each

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5
Q

characteristics to identify chromosomes?

A

size, banding pattern, position of the centromere

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6
Q

how are chromosomes numbered?

A

based on length, 1 is longest, 22 should be shortest (actually, 22 is longer than 21)

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7
Q

chromosome nomenclature:

short arm?

A

p

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8
Q

chromosome nomenclature:

long arm?

A

q

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9
Q

chromosome nomenclature:

region?

A

counting outward from centromere

within each region, have bands

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10
Q

chromosome nomenclature:

landmark?

A

consistent & distinct morphologic features

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11
Q

chromosome nomenclature:

bands?

A

division of regions

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12
Q

centromere is?

telomere is?

A

centromere: central condense region essential for itotic spindle attachment
telomere: terminal cap at end of each chromosome

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13
Q

what does p11.1 mean

A

p is short arm

1 is chromosome

2nd is region

3rd is subband

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14
Q

name parts of the chromosome/their function

A

short arm: p

long arm: q

telomere: cap/end of chromosome, helps chromosome keep its integrity; shortens with aging

subtelomeric region: region most prone to errors of deletions and duplications

center: centromere; different centromere locations can characterize diff chromosomes

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15
Q

metacentric vs. sub-metacentric vs. acrocentric chromosome?

A

metacentric: centromere in middle of equal p and q arms

sub-metacentric: p short, q longer

acrocentric: p arm essentially a satellite, doesn’t do much

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16
Q

what are dark/light bands on chromosomes?

A

dark: heterochromatin, inactive in transcription, not expressed, long repeats of many genes, thus more variable regions
light: euchromatin, more active txn area, where most active genes and crucial human disease genes are

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17
Q

which chromosomes have large heterochromatic regions?

A

1, 9, 16, Y

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18
Q

which chromosomes are acrocentric?

A

13, 14, 15, 21, 22

p arm is a satelle, nub, does not have important function - could lose satellite to no consequence for function

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19
Q

when in cell cycle can chromsomes be visualized?

A

metaphase

during active division

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20
Q

which cell types provide easy chromosome visualization?

A

dividing cells, in mitosis of cell cycle:

**T lymphocytes in blood which divide by phytohemagglutinin **

bone marrow cells

**fibroblasts from skin biopsies **

prenatal chorionic villi and fetal cells in amniotic fluid

products of conception (placental & fetal)

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21
Q

in what part of cell cycle do cells spend most of their time?

A

interphase

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22
Q

how long is cell cycle?

mitosis?

A

cell cycle: 24 hours

mitosis: 1-2 hours

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23
Q

what is chromosomal imbalance?

when is it most common?

A

imbalane in the amount of chromosomal material; may involve a few to 1000s (partial/whole chromosome) of genes, have catastrophic effects

most common in spermatogenesis, oogenesis

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24
Q

how can chromosomal imbalance mainfest?

A

1) whole or partial aneuploidy: gain or loss of a whole chromosome
2) abnormality may be in constitutional, non-mosaic, or mosaic state, which is less severe, = various chromosome complements in different cells
3) monosomy - one missing - is more devastating than trisomy - one extra

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25
Q

clinical phenotypes of chromosomal abnormalities

A

1) development delay/intellectual disability
2) alteration of facial morphogenesis to produce characteristic facial features
3) growth delay
4) malformations of internal organs - esp. cardiac

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26
Q

general effects of structural and numerical abnormalities - how do 1) loss of genetic material, 2) gain of genetic material, 3) relocation manifest?

A

1) loss of genetic material: deletion/monosomy
2) gain of genetic material: duplication/trisomy
3) relocation of genetic material: inversion/insertion/translocation

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27
Q

first trimester abortuses are mostly what kind of abnormality?

what kind of chromosomal abnormality dominates when fetus is born?

A

1st trimester: numerical - extra or missing chromosome, not structural issue

when fetus born: balanced/unbalanced abnormalities

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28
Q

why do chromosomal abnormalities occur more commonly in older than in younger women?

A

their eggs have been “frozen in time” for longer

error of nondisjunction more common when oocyte has been suspended for long time

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29
Q

what is most common cause of spontaneous abortions?

what trisomy is observed w/ this?

A

chromosomal imbalance causes 66% 1st trimester spontaneous abortion, 20% 2nd trimester spontaneous abortions

trisomy 16 most common trisomy observed; never seen in liveborn (except if mosaic)

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30
Q

ploidy?

A

addition or loss of **complete sets **of chromosomes

31
Q

euploidy?

A

normal diploid chromosomal state

32
Q

triploidy?

its cause?

what happens?

A

1 complete extra set of chromosomes

caused by polyspermy, fertilization of an egg by more than 1 sperm

usually spontaneously abort

digyny: extra haploid set is fro mmother; get IUGR, v. small placenta
diandry: extra haploid set is from father; get well grown fetus and large cystic complement

33
Q

tetraploidy?

cause?

what happens?

A

egg fertilized by 2 sperm

failure of first (early) zygotic division

lethal to embryo

other cell divisions may also fail to complete properly; small proportion of tetraploid cells can be in norma individuals (mosaicism)

34
Q

what are autosomal numerical abnormalities?

A

aneuploidy, monosomies, trisomies

35
Q

aneuploidy?

A

chromosome changes that don’t involve whole sets

usually consequence of failure of single chromosome (or bivalent) to complete division

problem in chromosomal copy number

36
Q

monosomies?

A

only 1 chromosome present in pair

all are lethal in early embryogenesis; abort too early to be recognized as conception

37
Q

trisomies?

what is risk factor for it?

A

meiosis I nondisjunction causes this

3 chromosomes instead of 2

incidence of trisomes rises sharply w/ increasing maternal age

38
Q

which full non-mosaic aneuploides are survivable?

A

trisomy 13

trisomy 18

trisomy 21

39
Q

what is nondisjunction?

A

disjunction: when chromosomes are paired off in middle, split, make 2 gametes

NON disjunction: chromosomal material stuck, 1 gamete has extra chromosome material, leads to a trisomy

40
Q

what causes trisomy 21

A

95% caused by **maternal meiosis I nondisjunction **

5% by parent carrying a Robertsonian translocation or mosaicism for Trisomy 21

75% spontaneously aborted

41
Q

if child has trisomy 18, what kind of gene do they have for it?

A

must be mosaic

otherwise too severe

= edward’s syndrome

42
Q

what is more common: sex chromosome or autosome aneuploidies?

A

sex chrom aneuploidies are more common and less severe than in autosomes

b/c of X-inactivation and paucity of genes on Y chromosome

43
Q

what is X-inactivation

A

when females turn off/silence 1 copy of genes on one X chromosome

makes gene dosage of X chromosome similar in males & females

44
Q

what are pseudoautosomal regions

A

genes on X-chromosome that’re also present on Y chromosome

these escape X-inactivation

occurs in: turner syndrome, klinefelter syndrome

45
Q

what is cause of turner syndrome?

incidence?

phenotype?

A

numerical abnormality causing 45,X - missing an X

very common, but 99% spontaneously aborted

phenotype: nondysmorphic mostly; coarctation of aorta; kidney issues; haplo insufficiency

46
Q

treatment for turney syndrome?

A

growth hormone & estrogen

47
Q

what causes most turner syndrome?

what are diff cytogenetic possibilities?

A

80% due to paternal meiotic error

45, X 50%

45,X/46,XX or 45,X/46,XY MOSAICS 30-40%

structural X abnormalities 10-20%

48
Q

what is cause of klinefelter syndrome? cause?

A

47,XXY

pseuatosomal region abnormality

problems w/ testicular function, decreased sexual characteristics, little spermatogenesis, ADHD

49
Q

what are 47,XYY males and 47,XXX females

A

examples of numerical abnormalities of sex chromosomes

both are essentially “normal”

50
Q

what is >3 copies of X chromosome associated w?

A

mental retardation

51
Q

uniparental dipoidy?

results?

A

when all chromosomes are inherited from 1 parent

if paternal: hydatidiform moles; only get trophoblast hyperplasia, no fetal parts

if maternal: from an activated unovulated oocyte; get ovarian tetroma, disorganized embryonic material

52
Q

uniparental disomy?

A

when person receives 2 copies of a chromosome, or of part of a chromosome, from 1 parent, and 0 copies from the other parent

affects single pair of chromosomes

usually causes problems in imprinted genes on specific chromosomes (6, 7, 11, 14, 15, 16)

usual cause is trisomy rescue

53
Q

what is trisomy rescue?

A

when fertilized ovum containing 3 copies of a chromosome loses 1 of these chromosomes to form a normal, diploid chromosome complement

if both retained chromosomes came from same parent, get univparental disomy

54
Q

types of structural rearrangements?

A

1) translocation
2) inversion
3) deletion/duplication
4) ring chromosome

55
Q

translocation?

A

interchange of genetic material between nonhomologous chromosomes

can be reciprocal/balanced: no phenotype usually, only phenotype if have disruption in break point

unbalanced: parital monosomy or partial trisomy - missing or extra piece

56
Q

what happens in a translocation carrier?

A

whereas normally sister chromatids line up as bivalent and then get normal chromosome segregation, translocation carriers form a tetrad of chromosomes

during separation or disjunction, get unbalanced translocation

57
Q

what are adjacent 1 and 2 outcomes?

A

outcomes of translocation carrier chromosome segregation

adjacent 1: unbalanced translocatoin

adjacent 2: centroemres from the same chromosome

58
Q

robertsonian translocation?

A

translocation between different acrocentric chromosomes (13 to 14, for ex)

short arms are lost, long arms fuse at centromere

occurs in 5% of Down Syndrome cases

considered balanced b/c no missing chromosomal material!

59
Q

inversions?

types?

A

2 breaks in 1 chromosome

area between the breaks is inverted, then reinserted, the breaks unite then to rest of chromosome; can be terminal- to end of chromosome, or interstitial- within the long or short arm

**pericentric inversion: **if inverted area includes centromere

paracentric inversion: if inverted area doesn’t include centromere

can cause deletions, duplications

60
Q

what do inversions cause?

A

deletions, duplications

61
Q

deletion is?

A

loss of a chromosome segment

can be interstitial or terminal

62
Q

wolf-hirschhorn syndrome is ex. of?

A

deletion of 4p16.3

63
Q

ring chromosomes?

A

when pieces on top of chromosmoe fall off, join into a ring shaped chromosome

Ring X r(X) is most common, causes Turney syndrome in most cases

64
Q

“viable” chromosome imbalances?

A

unbalanced translocations: partial monosomy & partial trisomy

deletions: partial monosomy
duplications: partial trisomy
ring: partial monosomy

recombinant inversion derivatives: partial monosomy & partial trisomy

65
Q

what is FISH

A

FISH = flourescence in situ hybridization

physical DNA mapping technique

DNA probe labeled w/ marker molecule is hybridized to chromosomes on a slide, visualized using flourescence microscope

marker molecule is floursescent or detected w/ fluourescently labeled antibody

66
Q

FISH hybridization steps?

A

denature ds DNA, generate single-stranded DNA

probe w/ fluorochrome DNA probe of bases

probe recognizes target DNA sequences

probe hybridizes to target DNA sequences

67
Q

FISH applications?

A

chromosome identification

aneuploidy detection in prenatals

marker chromosome identification

total chromsome analysis

translocation analysis

microdeletion syndrome analysis

gene amplification analysis in cancer

68
Q

what is FISH used to study?

A

good to est. deletion, duplication of genomic regions too small to be detected by karyotype analysis

particularly: recurrent microdeletion syndromes caused by unequal crossing over events at susceptible regions of the genome

confirmation, not diagnosis of genomic disorders involving microdeletion/duplication syndromes

ie DiGeorge Syndrome - deletion of single gene on 22q11 or Wilms tumor, caused by deletion of series of adjacent genes on 11p13

69
Q

cause of DiGeorge/Velo-cardio-facial syndrome?

A

22q11 deletion

70
Q

array CGH usefulness?

what isn’t it good for?

A

**genome-wide view of copy number variations **

helps to find cause for selected conditions ie of intellectual disability and multiple congenital anomalies; standard of care used rather than karyotype

cannot detect chromosomal anomalies that mintain normal copy numer (balance translocation, inversions); does not provide data on repeat-rich regions (centromeres, hterochromatin)

71
Q

what is meiosis?

A

meiosis I: process by which recombination of chromosomes occurs in germ cells

meiosis II: yields mature haploid oocytes and spermatogonia

72
Q

why do trisomies/monosomies occur?

A

failure to properly segregtae chromosomes during each division step of meiosis

leads to abnormal copy number in resulting conceptus

73
Q

are autosomal numerical abnormalities viable? why/why not?

A

usually, not

because large alterations in gene dose occur

74
Q

what causes most trisomies?

A

95% trisomies are due to meiotic non-disjunction

75% occur during meiosis I

MCG (77 decks)

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