Chromosome abnormalities and genomic rearrangements

Question 1

What is cytogenietics and what does it look at

Answer 1

study of chromosomes

number, structure, deletions, duplications, instability

Question 2

what are the types of chromosome abnormalities

Answer 2

chromosome rearrangements, whole chromosome aneuploidy, copy number imbalance

Question 3

what are the techniques used to investigate chromosomess

Answer 3

traditional cytogenetics (cell culture required to collect metaphase cells):
G banding, some FISH, breakage
molecular cytogenetics (tests carried out on DNA):
QF-PCR, MLPA, array CGGH

Question 4

What problems can chromosome rearrangements, copy number imbalance, chromosome breakage syndrome cause

Answer 4

chromosome rearrangement: recurrent miscarriage, infertility
copy number imbalance: dysmorphism, developmental delay, learning difficulties, specific phenotypes e.g. epilepsy, diabetes, cardiac malformations
chromosome breakage ssyndromes: facnconi anaemia, ataxia telangiectasia

Question 5

what does whole chromosome aneuplodiy arise from and what does it cause

Answer 5

arises following nondisjunction at mitosiss or meiosis

large genomic imbalannce leads to loss of conceptions

Question 6

What does nondissjunction of homologous chromosomes in meiosis I cause

Answer 6

disomic and nullisomic gamete formation

Question 7

what do the following become:
disomic+normal
nullisomic+normal
disomic+nullisomic

Answer 7

disomic+normal=trisomic conceptus
nullisomic+normal=monosomic conceptus
disomic+nullisomic=uniparental disomy

Question 8

what is mosaicism and how does it arise in an initially normal conceptus

Answer 8

presence of 2 diff. genotypes from individual arising from single egg due to nondisjunction or anaphase lag

Question 9

what are the types of mosaicism

Answer 9

somatic-likely to result in abnormal phenotype
gonadal: arises during formation of germ cells
CPM: mosaicism confined to extraembryonic tissue

Question 10

what are the types of chromosome rearrangements

Answer 10

robertsonian translocation, reciprocal translocation, inversion, intrachromosomal insertions

Question 11

what does robertsonian translocation arise from and how are balanced carriers phenotypes and reprouctive rissks

Answer 11

fusion of 2 acrocentric chromosomes.(13, 14, 15, 21, 22).
balanced carriers are phenotypicallly normal but have reproductive risks (recurrent miscarriages, patau syndrome, down syndrome, male infertility)

Question 12

What are the most common robertsonian translocations

Answer 12

der (13;14) der (14;21)

Question 13

what does reciprocal translocation arise from and how are balanced carriers phenotypes and reprouctive rissks

Answer 13

can be between any segments of any nonhomologous chromosomes
balanced carriers=phenotypically normal but have reproductive risks (infertility, miscarriage, child with congenital abnormalities)

Question 14

What types of reciprocal translocations are there, draw it out

Answer 14

alternate segregation, adjacent 1 segregation, 3:1 segregatipn

Question 15

what is a chromosome inversion and what types of chromosome inversions are there

Answer 15

when segment of chromosome rearranged end to end
Paracentric inversions do not include the centromere and both breaks occur in one arm of the chromosome. Pericentric inversions include the centromere and there is a break point in each arm.

Question 16

Fluorescence In Situ Hybridisation what does it do

Answer 16

uses fluorescent probes that bind to only those parts of a nucleic acid sequence with a high degree of sequence complementarity

Question 17

What is G banding

Answer 17

produce a visible karyotype by staining condensed chromosomes.

Question 18

which tests are used for prenatal cytogenetics

Answer 18

traditionally G banding but results needed more quickly so FISH and WF-PCR

Question 19

What does QF-PCR

Answer 19

amplify specific regions of DNA and quantify the amount of DNA present in those regions.

Question 20

In terms of QF-PCR, draw sketches of the results for: disomy 1:1, trisomy 2:1, trisomy 1:1:1, uninformative 1:1 or 1:1:1

Answer 20

ref. notes
disomy 1:1 2 homologues different size
trisomy 2:1 if 3 homologues and 2 of them same length
trisomy 1:1:1 if all have different length marker
uninformative 1:1 or 1:1:1

Question 21

for segmental copy no. imbalance, what are the numbers for: normal, deletion, duplication, triplication

Answer 21

normal=x2
deletion=x1 or x0
duplication=x3
triplication=x4

Question 22

give examples of microdeletion syndromes and what it effects

Answer 22

DiGeorge-dell(22q)
Williams-del(7q)
Angelman-del(15q)
Prader-willi-del(15q)
Wolf-Hirschhorn-del(4p)

Question 23

Array CGH what it detects

Answer 23

whole chromosomes aneuploidy, microdeletion/duplication syndromes, subtelomere imbalance, other regions of imbalance (copy number variants)

Question 24

How to ascertain clinical consequences of previously unreported imbalance

Answer 24

ineritance (de novo and inherited from affected=more likely to be pathogenic, inherited from unaffevcted more likely to be benign), number of genes (burden), specific gene content (correlation with phenotype)