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GBE > GEN: Chromosome Abnormalities and Genomic Rearrangements > Flashcards

GEN: Chromosome Abnormalities and Genomic Rearrangements Flashcards

1
Q

what is the study of chromosomes called?

A

cytogenetics

number, strucutre, deletions, duplications, instability

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2
Q

why has it been difficult to establish chromsome numbers in the past?

A

karyotyping techniques produced low quality images

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3
Q

what is aneuploidy?

A

any number of chromosomes in humans that is not 46

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4
Q

what 3 kind of chromosome abnormalities can you have?

A
  1. chromosome rearrangements
  2. whole chromosome aneuploidy
  3. copy number imbalance (missing/extra)
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5
Q

what 2 techniques are used to investigate chromosomes?

A

traditional cytogenetics

molecular cytogenetics

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6
Q

whats involved in traditional cytogenetics

A

G-banding

fluorescence in situ hybridisation (FISH)

breakage

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7
Q

whats involved in molecular cytogenetics

A

Quantitative Fluorescence-PCR

MLPA

Array CGH

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8
Q

what is required for traditional cytogenetics?

A

cell culture to collect metaphase cells

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9
Q

what are molecular cytogenic tests carried out on?

A

DNA

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10
Q

what does this image show?

A

G-banded chromosomes

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11
Q

what are consequences of chromosome rearrangements?

A

recurrent miscarriages and infertility (meiosis issues)

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12
Q

what are consequences of copy number imbalances?

A

dysmorphism, developmental delays, learning difficulties, specific phenotypes (epilepsy, diabetes, cardiac malformations)

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13
Q

what are consequences of chromosome breakage syndromes?

A

fanconi anaemia, ataxia telangiectasia

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14
Q

how does whole chromosome aneuploidy arise?

A

non-disjunction at meiosis/mitosis

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15
Q

why are chromosomes 13, 18 and 21 the live birth autosomal trisomies?

A

as they are gene-poor chromosomes as large genomic imblanaces lead to conception loss

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16
Q

what happens in meiosis I and II?

A
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17
Q

how do trisomic conceptus come about?

A
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18
Q

how do monosomic conceptus come about?

A
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19
Q

how do uniparental disomy’s come about?

A
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20
Q

when does uniparental disomy become important?

A

if chromosome carries imprinted gene

21
Q

what can you get mosaicism from?

A

whole chromosome aneuploidy

22
Q

what is mosaicism?

A

anaphase lags in cell division from an aneuploid cell so one cell line/daughter cell losing its extra chromosome ⇒ normal chormosome complement

23
Q

what else can mosaicism arise from other than whole chromosome aneuploidy

A

can arise in an initially normal conceptus. This can be due to either non-disjunction or
anaphase lag.

24
Q

what happens if it is a somatic conception in mosaicism

A

abnormal phenotype improved by normal cell line

25
Q

what happens if it is a gonadal conception in mosaicism?

A

arises in germ cells identified by 2 pregnancies with same de novo abnormality

26
Q

what happens if it is a CPM in mosaicism?

A

confined to extraembryonic tissue, can have normal outcome or compromise placental function, may also result in UPD following trisomy rescue

27
Q

what 4 chromosome rearrangements can you have?

A
  • Robertsonian translocations
  • reciprocal translocations
  • inversions
  • intrachromosomal insertions
28
Q

what are Robertsonian translocations?

A

fusions of two acrocentric chromosomes (13, 14, 15, 21, 22) where balanced carriers are phenotypically normal but have reproductive risks - recurrent miscarriages, Patau syndrome, Down syndrome and male infertility

29
Q

what are reciprocal translocations?

A

any segment of non-homologous chromosomes, almost always unique to the family where balanced carriers are phenotypically normal but have reproductive risks

30
Q

what are the reproductive risks of reciprocal translocations dependent on?

A

size of translocated segment

31
Q

what are the two inversion types?

A

pericentric - including centromere

paracentric - excluding centromere

32
Q

what happens in ‘Fluorescence In Situ Hybridization’
(FISH)

A

denaturation and re-annealing

33
Q

what can FISH be used for?

A

investigation of structurally abnormal chromosomes using FISH

looking for specific deletions

34
Q

what is segmental copy number imbalance?

A

imbalance of bits within chromosome

34
Q

what was the traditional prenatal cytogenetics test?

A

G banded chromosomes, which requires 2 weeks for results

34
Q

what can be used instead the traditional prenatal cytogenetics test?

A

FISH, QF-PCR: more accurate

35
Q

what is the resolution for G-banded chromosome analysis?

A

~5-10Mb

36
Q

what causes syndromic disease?

A

many small imbalances (microdeletions) - cannot pick up via G-banding

37
Q

what are microdeletion syndromes?

A
  • submicroscopic chromosomal deletions (100-3000kb)
  • called syndrome because they occur at low freq. in all populations
38
Q

why does microdeletion happen?

A

genomic structure at disease locus predisposing gene to deletion-duplication by unequal recombination

39
Q

what are microdeletions mediated by

A

low copy repeats

40
Q

what are 5 micro deletion syndromes?

A
41
Q

what test detects microdeletions?

A

Array CGH

42
Q

how does array CGH work

A
  1. chop up and label patients DNA with fluorescent marker red
  2. chop up reference DNA and label with green
  3. apply both to microarray slide
  4. denature and re-anneal to complementary oligonucleotide sequences
  5. red= more patient ⇒ duplication, green=more control ⇒ deletion
  6. plotting
43
Q

what 4 things can array CGH detect

A
  • whole chromosome aneuploidy
  • micro deletion/duplication syndromes
  • subtelomere imbalance
  • other imbalance regions (CNVs -maybe benign or pathogenic)
44
Q

what does array CGH not give?

A

position effect - G-banding is used for infertile males

45
Q

how can we determine the clinical consequence of a previously unreported imbalance?

A
  • inheritance
    • de novo or inherited from affected parent ⇒ pathogenic
    • inherited from unaffected parent ⇒ benign
  • number of genes (burden)
  • specific gene content (phenotype correlation?)
46
Q

what will array CGH soon be replaced by

A

Whole exome/genome sequencing (NGS)

GBE (58 decks)

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