G8

Question 1

describe an autosomal dominant inheritance and and give an example

Answer 1

half of offspring affected
unaffected individual doesnt transmit disease
eg. Anchroplasia - dwarfism

Question 2

describe an autosomal recessive inheritance and give an example

Answer 2

ussually only one generation affected
if both parents carriers = 1/4 affect, 1/2 carries, 1/4 not affects
eg. CF

Question 3

What is X linked recessive inheritance and give an example

Answer 3

carrier females transmit disease to half their sons and carrier status to half their daughters
eg. X linked haemophilia

Question 4

c.76A>T

Answer 4

substitution A->T in coding DNA

Question 5

c.76_78delACT

Answer 5

range of affected resieus 76-78 by deletion of ACT

Question 6

c.76dupA

Answer 6

duplication at 76 of A base

Question 7

c.76delA

Answer 7

deletion at 76 of A

Question 8

c.76-83inv

Answer 8

inversion between 76 and 83

Question 9

c.76_77insG

Answer 9

insertion but it duplication describe as duplication

G inserted between 76 adn 77

Question 10

p:Lys76Asn

Answer 10

p refers to primary translation product

at AA 76 varient results in sub of asparagine instead of normal lysine

Question 11

p.Tyr356X

Answer 11

X indicates a nonsense codon has been generated

Question 12

c.1408+2T>G

Answer 12

second nucleotide after c.1408 that would normally be the invariant T of splice site is insead a G

Question 13

c.789-1G>A

Answer 13

first nucletodie before c.780 that would normally be invariant G of splice site is now an A

Question 14

c.69_71del(p.Val15del)

Answer 14

in frsame deletion deletes aa valine

Question 15

c.546insA(p.Val170fs)

Answer 15

out of frame insertion inserted valine causing frameshift after 170

Question 16

what letters denote each type of reference seqeunce

Answer 16

c= coding DNA
g- genomic DNA
r = coding RNA reference seq
n = non coding RNA ref seq
m = mitochondrial DNA seq

Question 17

What is HGVS

Answer 17

human genome variation society

Question 18

what terms do HGVS use to prevent confusion from using terms like SNP or mutation

Answer 18

sequence variatn
alteration
allelic variant

Question 19

what classes and terms do HGVS use to recognise that some variants can be harmful

Answer 19

5 = affects function
4 = probs affects function
3 = unknown
2- probs doesnt affect function
1= doesnt affect function

Question 20

what casues anchrondoplasia

Answer 20

Fibroblast growth factor receptor 3 p FGFR3 - represses ossification of chondrocytes that proliferate and mature into bones at growth plate
- in anchondroplasia ossification is further pressed

Question 21

what is ossification

Answer 21

process where catilage is turned into bone

Question 22

why is it difficult to predict what the ouctome of splice site mutations will be?

Answer 22

as genes use alternate transcriptional start sites, alternate combos of exons, althhough usually one isoform RNA is shown, cell can produce several different ones at the same time and this remains poorly understood

Question 23

what is nonsense mediated decay?

Answer 23

highly conserved quality control survelliance mechanism
recongises and degrades defective mRNAs with premature termination codons PTCs which if translated could produce harmful aberrant proteins
(can occur indep of any DNA mutations as a result of errors during transcription, processing or packaging)

Question 24

what happens to EJCs in normal splicing and i PTC containing mRNA

Answer 24

normal: proteins of exon junction complec = deposited 2-24 nts upstream of each exon/exon unction, and are displaced by scanning ribosome during inital round of translation.
PTC: upon recognition of stop codon, a termination complex is fomred, in PTC containing mRNA, EJCS downstream of PCR are not displaced allowing the termination complex to interact with the EJC triggering NMD.

Question 25

why do premature stop codons lead to

Answer 25

not neccessarily truncated proteins = often no protein at all through NMD

Question 26

What could PTC read through do?

Answer 26

override NMD degradation mechanisms and allow some proteins to be produced from mutant mRNAs - pioneered in the field of DMD = clinical practice

Question 27

what do most cases of CF result from

Answer 27

phe580del change in F508, 3nt deletion, deleting phenylalanine at position 508. created a misfolded protein which is usually degraded in ER, poorly function if does reach cell surface.

Question 28

what kind of mutation is DMD usually caused by

Answer 28

frameshift and nonsense mutations

Question 29

what kind of mutation is backer muscular dystrophy caused by

Answer 29

inframe deletion or change in expression

Question 30

how is it theoretically possible to convert faulty mRNA to produce product

Answer 30

inducing exon skips using antisense constructs and produce an inframe mutation without the framshift nonsense codon

Question 31

what can inframe deletions be

Answer 31

1. disease causing as in CFTR - Phe508 2. better than no protein at all as in dystrophin 3. tolerated with no apaprent ill effect (as heterozygote)

Question 32

Describe the case study of the mutation on ENG

Answer 32

endoglin gene (ENG) causing HHT - autosomal dominant disease causing nosebleeds and abnormal blood vessels, only 2/3 children had HHT = not possible, so found that it was just an endoglin missense polymorphism that had been overinterpreted, seqeunce change was not in pahse with true diesease causing gene.