Chromosome Pathologies

Question 1

what is cytogenetics

Answer 1

study of chromosomes, anything larger than a single gene

Question 2

what do most cytogenic changes result due to

Answer 2

copy number variations - gain or loss of genetic material - usually pathogenic range varies from 1kb o severe mb
may be familial or de novo

Question 3

what 4 causes of cryogenic abnormalities produce abnormal phenotype e

Answer 3

dosage effect ( deletion or duplication - lose more disruptive than gain)

disruption of a gene (inappropriate activation or inactivation)

position effect - gene in new chromosomal environment

unmasking of a recessive disorder

Question 4

what are the types of CNV’s (copy number variations)

Answer 4

aneuploidy - gain (trisomy) or los (monosomy) of one chromosome

polyploidy - gain whole sets ie triploidy or tetraploidy)

mosacisim - diploidy ( normal) and (aneuploidy) - different genetic material in the same individual

Question 5

what are the there origins of numeric abnormalities

Answer 5

gametogenesis (meiosis) - failure of homologous chromosome (M1 or 2) to separate properly during cell division

fertilisation

early cleavage ( post-zygotic MITOTIC non-disjunction)

Question 6

what is autosomal aneuploidy and give 3 examples

Answer 6

error at gametogenesis
trisomy 21 - downs
trisomy 18 - edwards
trisomy 13 - patau

80-90% caused by non-disjunction at meiosis 1

Question 7

how does age affect risk of autosomal aneuploidy

Answer 7

increase in maternal age increases risk but paternal age has no significant risk

Question 8

what is sex chromosome aneuploidy

Answer 8

phenotype less severe than autosomal, sexual orientation not affected 
turners syndrome (45,X), kleinfelters (47 XXY)

Question 9

what is polyploidy, origin and examples

Answer 9

error at fertilisation
mostly triploidy - 69 XXY, 69 XYY, 69 XXX
origin - digyny (double female) , diplospermy (2N in sperm) , dispermy (two sperm)
double paternal = large cystic placenta, some growth delay
double maternal = tiny placenta, significant growth delay, head saving macrocephaly

Question 10

what is moisacisim

Answer 10

error at early cleavage - mitotic non-disjunction

variable phenotype - produces on-identical twin
may generate uniparental disomy (UPD)

all females are mosaic - 2X chromosomes where one randomly inactivates

Question 11

how often are structural defects in DNA such as duplication or deletion
what test is used to detect this

Answer 11

1/2000
duplication smaug be direct or inverted
detected using microarray CGH

Question 12

describe the process of microarray CGH

Answer 12

hybridise sample and control DNA to microarray “chip”

genomic imbalances (CNV’s) are produced at high resolution

red bars show loss and green bars show gain

Question 13

how are haploinsufficinecy sores determined

Answer 13

for deleted regions, low scores indicate greater likelihood of pathogenicity - only relevant in dominant alleles

Question 14

who are microarray CGH testing used for, advantages and disadvantages

Answer 14

children of moderate and severe learning disability and pregnancies with abnormal ultrasound

ad - early diagnosis, higher resolution, greater accuracy

dis - gives info on dosage change only, no info on mutation, needs quality DNA

Question 15

what technique is used for aneuploidy detection

Answer 15

quantitative fluorescent PCR (QF-PCR)

PCR of Short tandem repeats (STR) using fluorescent primers

Question 16

describe the process of QF-PCR

Answer 16

DNA extraction from prenatal or blood sample
PCR amp - primers forms chromosomes with 13,18,21, X and Y
aneuploidy is expressed as a result when 2 markers with abnormal dosage = 2:1 ratio of peak height indicates trisomy

Question 17

what is NIPT

Answer 17

non-invasive prenatal testing

maternal blood samples - extract free fetal DNA - if risk of aneuploidy do invasive test then QF-PCR

Question 18

what is cancer and gives examples of how you test for it

Answer 18

disease specific acquired chromosomal changes - mostly translocations
eg leukeamia - bone marrow
solid tumour - tumour tissue

Question 19

what are the two types of chromosomal inversions

Answer 19

paracentric - inversion on one arm ( breakpoints on same arm)

pericentric - inversion across both arms (breakpoints on different arms)

Question 20

what are the two types of translocations

Answer 20

reciprocal - break and exchange

robertsonian - whole arm fusion

Question 21

describe a reciprocal translocation

Answer 21

break and exchange of parts - 1/500, 5-10% phenotype risk

reproductive risk ie balanced translocation so carrier but not in phenotype

Question 22

describe a robertson ian translocation

Answer 22

whole arm fusion 
1/1000
occurs across acrocentric chromosomes 
no phenotype risk 
reproductive risk - carriers

Question 23

how do we name translocations

Answer 23

eg between 4 and 8

if balanced - don’t need to show anything else

der(4) = one chromosome 4 is a derivative chromosome - it has a change in its structure (in this example piece missing and replaced with something from 8

ie der(4)t(4;8) = unbalanced translocation of chromosomes 4 and 8 where one chromosome 4 is derivative and contains some missing of 4 replaced with some of 8