Haemophilia and related disorders

Question 1

what can abnormal haemostasis result in

Answer 1

thrombophilia + bleeding disorders

Question 2

what is thrombophilia

Answer 2

abnormal tendancy to develop blood clots

Question 3

what factor is damaged in haemophilia A

Answer 3

factor 8

Question 4

what are the 3 phenotype groups for haemophilia and what do they correlate with

Answer 4

1. mild
2. moderate
3. severe
   correlate closely with the level of function of the affects coagulation factor -> in turn depends on the site/type of the mutation

Question 5

what is the most common structual variant that is seen in haemophillia

Answer 5

flip-tip-inversion; regularly occurs as a new mutation during male meiosis

Question 6

are new mutation rates equal throughout the genome and why

Answer 6

no - particular DNA sequences may have features/motifs that increase mutation rates

Question 7

where does the flip-tip-inversion occur

Answer 7

end of the x-chromosome

Question 8

describe how the flip-tip inversion occurs (see lect for diagram)

Answer 8

there are 3 homologous transcribed sequences on the chromosome, one of which lies within the factor 8 gene -> allows for intrachromosomal recombination during meoisis (usually between paired chromosomes but in men there is only 1 X chromosome) -> the recombination leads to an inversion of the F8 gene, with the end of the X chromosome completely flipping over for this to happen -> gene is broke -> severe haemophilia

Question 9

if a man has haemophilia, what will the genetics of his son + daughter be (affected, carrier, normal etc.) -presuming mother is not a carrier

Answer 9

haemophilia is an X linked recessive disease =>
son - will be unaffected as he inherits his only X chromosome from the mother;
daughter - will be an obligate carrier (inherits an X from each parted => will definately inherit and affected chromosome

Question 10

what can be offered if there is a known risk of severe genetic disease in pregnancy

Answer 10

genetic testing - chronic villus sampling (CVS) or non-invasive methods (NIPD/NIPT)

Question 11

how does NIPD detect genetic diseases in the unborn child

Answer 11

fragments of cfDNA (cell free DNA) are in the mother’s blood - some are hers and some come from the placenta (i.e. are those of the foetus) -> cfDNA extracted and tested for specific genetic conditions (including down syndrome, turner syndrome, keinfelter syndrome)

Question 12

2 functions of von willebrand factor

Answer 12

It promotes adhesion of platelets to a damaged endothelium; It is a carrier molecule for circulating factor 8