GEN: Chromosome Abnormalities and Genomic Rearrangements

Question 1

what is the study of chromosomes called?

Answer 1

cytogenetics

number, strucutre, deletions, duplications, instability

Question 2

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

Answer 2

karyotyping techniques produced low quality images

Question 3

what is aneuploidy?

Answer 3

any number of chromosomes in humans that is not 46

Question 4

what 3 kind of chromosome abnormalities can you have?

Answer 4

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

Question 5

what 2 techniques are used to investigate chromosomes?

Answer 5

traditional cytogenetics

molecular cytogenetics

Question 6

whats involved in traditional cytogenetics

Answer 6

G-banding

fluorescence in situ hybridisation (FISH)

breakage

Question 7

whats involved in molecular cytogenetics

Answer 7

Quantitative Fluorescence-PCR

MLPA

Array CGH

Question 8

what is required for traditional cytogenetics?

Answer 8

cell culture to collect metaphase cells

Question 9

what are molecular cytogenic tests carried out on?

Answer 9

DNA

Question 10

what does this image show?

Answer 10

G-banded chromosomes

Question 11

what are consequences of chromosome rearrangements?

Answer 11

recurrent miscarriages and infertility (meiosis issues)

Question 12

what are consequences of copy number imbalances?

Answer 12

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

Question 13

what are consequences of chromosome breakage syndromes?

Answer 13

fanconi anaemia, ataxia telangiectasia

Question 14

how does whole chromosome aneuploidy arise?

Answer 14

non-disjunction at meiosis/mitosis

Question 15

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

Answer 15

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

Question 16

what happens in meiosis I and II?

Answer 16

Question 17

how do trisomic conceptus come about?

Answer 17

Question 18

how do monosomic conceptus come about?

Answer 18

Question 19

how do uniparental disomy’s come about?

Answer 19

Question 20

when does uniparental disomy become important?

Answer 20

if chromosome carries imprinted gene

Question 21

what can you get mosaicism from?

Answer 21

whole chromosome aneuploidy

Question 22

what is mosaicism?

Answer 22

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

Question 23

what else can mosaicism arise from other than whole chromosome aneuploidy

Answer 23

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

Question 24

what happens if it is a somatic conception in mosaicism

Answer 24

abnormal phenotype improved by normal cell line

Question 25

what happens if it is a gonadal conception in mosaicism?

Answer 25

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

Question 26

what happens if it is a CPM in mosaicism?

Answer 26

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

Question 27

what 4 chromosome rearrangements can you have?

Answer 27

- Robertsonian translocations - reciprocal translocations - inversions - intrachromosomal insertions

Question 28

what are Robertsonian translocations?

Answer 28

**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

Question 29

what are reciprocal translocations?

Answer 29

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

Question 30

what are the reproductive risks of reciprocal translocations dependent on?

Answer 30

size of translocated segment

Question 31

what are the two inversion types?

Answer 31

pericentric - including centromere paracentric - excluding centromere

Question 32

what happens in 'Fluorescence In Situ Hybridization' (FISH)

Answer 32

denaturation and re-annealing

Question 33

what can FISH be used for?

Answer 33

investigation of structurally abnormal chromosomes using FISH looking for specific deletions

Question 34

what is segmental copy number imbalance?

Answer 34

imbalance of bits within chromosome

Question 34

what was the traditional prenatal cytogenetics test?

Answer 34

G banded chromosomes, which requires 2 weeks for results

Question 34

what can be used instead the traditional prenatal cytogenetics test?

Answer 34

FISH, **QF-PCR**: more accurate

Question 35

what is the resolution for G-banded chromosome analysis?

Answer 35

~5-10Mb

Question 36

what causes syndromic disease?

Answer 36

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

Question 37

what are microdeletion syndromes?

Answer 37

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

Question 38

why does microdeletion happen?

Answer 38

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

Question 39

what are microdeletions mediated by

Answer 39

low copy repeats

Question 40

what are 5 micro deletion syndromes?

Answer 40

Question 41

what test detects microdeletions?

Answer 41

Array CGH

Question 42

how does array CGH work

Answer 42

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

Question 43

what 4 things can array CGH detect

Answer 43

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

Question 44

what does array CGH not give?

Answer 44

position effect - G-banding is used for infertile males

Question 45

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

Answer 45

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

Question 46

what will array CGH soon be replaced by

Answer 46

Whole exome/genome sequencing (NGS)