LEC42: Inborn Errors of Development: Chromosomes and Cytogenetics Flashcards Preview

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Flashcards in LEC42: Inborn Errors of Development: Chromosomes and Cytogenetics Deck (74):
1

cytogenetics?

study of chromosomes 

mechanisms of chromosomal disorders (microscopic & submicroscopic)

2

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

2/3

3

what % of cardiac defects do chromosome abnormalities cause?

20% of pts w/ cardiac defects

4

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

individiuals w/ autism and cardiac defects?

intellectual disability: 20-30% 

autism, cardiac defects: 20% each

5

characteristics to identify chromosomes?

size, banding pattern, position of the centromere 

6

how are chromosomes numbered?

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

7

chromosome nomenclature:

short arm?

p

 

8

chromosome nomenclature:

long arm?

q

9

chromosome nomenclature:

region?

counting outward from centromere

within each region, have bands

10

chromosome nomenclature:

landmark?

consistent & distinct morphologic features

11

chromosome nomenclature:

bands?

division of regions 

 

12

centromere is?

telomere is?

centromere: central condense region essential for itotic spindle attachment 

telomere: terminal cap at end of each chromosome

13

what does p11.1 mean

p is short arm 

1 is chromosome 

2nd is region 

3rd is subband 

14

name parts of the chromosome/their function

 

Q image thumb

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 

15

metacentric vs. sub-metacentric vs. acrocentric chromosome?

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 

 

A image thumb
16

what are dark/light bands on chromosomes?

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

17

which chromosomes have large heterochromatic regions?

1, 9, 16, Y

18

which chromosomes are acrocentric?

13, 14, 15, 21, 22

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

19

when in cell cycle can chromsomes be visualized?

metaphase

during active division

20

which cell types provide easy chromosome visualization?

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)

21

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

interphase

22

how long is cell cycle? 

mitosis? 

 

cell cycle: 24 hours 

mitosis: 1-2 hours

23

what is chromosomal imbalance? 

when is it most common?

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

24

how can chromosomal imbalance mainfest?

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

25

clinical phenotypes of chromosomal abnormalities

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

26

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

1) loss of genetic material: deletion/monosomy 

2) gain of genetic material: duplication/trisomy 

3) relocation of genetic material: inversion/insertion/translocation

27

first trimester abortuses are mostly what kind of abnormality?

what kind of chromosomal abnormality dominates when fetus is born?

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

when fetus born: balanced/unbalanced abnormalities

28

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

their eggs have been "frozen in time" for longer 

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

29

what is most common cause of spontaneous abortions? 

what trisomy is observed w/ this?

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)

30

ploidy?

addition or loss of complete sets of chromosomes

31

euploidy?

normal diploid chromosomal state

32

triploidy? 

its cause? 

what happens?

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

tetraploidy? 

cause? 

what happens?

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

what are autosomal numerical abnormalities?

aneuploidy, monosomies, trisomies

35

aneuploidy?

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

monosomies?

only 1 chromosome present in pair

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

37

trisomies?

what is risk factor for it?

meiosis I nondisjunction causes this 

3 chromosomes instead of 2

incidence of trisomes rises sharply w/ increasing maternal age

38

which full non-mosaic aneuploides are survivable?

trisomy 13

trisomy 18

trisomy 21

39

what is nondisjunction?

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

what causes trisomy 21

95% caused by maternal meiosis I nondisjunction 

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

75% spontaneously aborted 

41

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

must be mosaic 

otherwise too severe

= edward's syndrome

42

what is more common: sex chromosome or autosome aneuploidies?

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

what is X-inactivation

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

makes gene dosage of X chromosome similar in males & females

44

what are pseudoautosomal regions

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

these escape X-inactivation 

occurs in: turner syndrome, klinefelter syndrome

45

what is cause of turner syndrome?

incidence?

phenotype?

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

treatment for turney syndrome?

growth hormone & estrogen

47

what causes most turner syndrome? 

what are diff cytogenetic possibilities?

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

what is cause of klinefelter syndrome? cause?

47,XXY 

pseuatosomal region abnormality

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

49

what are 47,XYY males and 47,XXX females

examples of numerical abnormalities of sex chromosomes

both are essentially "normal" 

 

50

what is >3 copies of X chromosome associated w?

mental retardation

51

uniparental dipoidy? 

results?

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

uniparental disomy?

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

what is trisomy rescue?

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

types of structural rearrangements?

1) translocation

2) inversion 

3) deletion/duplication 

4) ring chromosome

55

translocation?

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

what happens in a translocation carrier?

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

what are adjacent 1 and 2 outcomes?

outcomes of translocation carrier chromosome segregation 

adjacent 1: unbalanced translocatoin

adjacent 2: centroemres from the same chromosome

58

robertsonian translocation?

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!

 

A image thumb
59

inversions?

types?

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

what do inversions cause?

deletions, duplications

61

deletion is?

loss of a chromosome segment 

can be interstitial or terminal

62

wolf-hirschhorn syndrome is ex. of?

deletion of 4p16.3

63

ring chromosomes?

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

"viable" chromosome imbalances?

unbalanced translocations: partial monosomy & partial trisomy

deletions: partial monosomy 

duplications: partial trisomy 

ring: partial monosomy 

recombinant inversion derivatives: partial monosomy & partial trisomy

65

what is FISH

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

FISH hybridization steps?

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

FISH applications?

chromosome identification

aneuploidy detection in prenatals 

marker chromosome identification

total chromsome analysis 

translocation analysis

microdeletion syndrome analysis

gene amplification analysis in cancer

68

what is FISH used to study?

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

cause of DiGeorge/Velo-cardio-facial syndrome?

22q11 deletion 

 

70

array CGH usefulness?

what isn't it good for? 

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

what is meiosis?

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

meiosis II: yields mature haploid oocytes and spermatogonia

72

why do trisomies/monosomies occur?

failure to properly segregtae chromosomes during each division step of meiosis 

leads to abnormal copy number in resulting conceptus 

73

are autosomal numerical abnormalities viable? why/why not?

usually, not

because large alterations in gene dose occur

74

what causes most trisomies?

95% trisomies are due to meiotic non-disjunction 

75% occur during meiosis I 

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