DNA mutations

Question 1

types if variant

Answer 1

duplications of genes or parts of them

deletions

variants within regulatory sequence

splice site variants

premature stop codon-nonsense variant

mis-sense variant

expansion of trinucleotide repeats

Question 2

deletions

Answer 2

out of frame deletion clearly disrupts the protein

in frame deletion

Question 3

out of frame deletion + example

Answer 3

one letter being deleted

absence of dystrophin in DMD

Question 4

in frame deletion + example

Answer 4

deletion of 1 whole codon

milder Becker Muscular dystrophy

Question 5

splice site variant

Answer 5

affects accurate removal of an intron

Question 6

non-sense variant

Answer 6

change codon to stop

out of frame deletion produces stop codon at deletion site or further along

RNA detaches from ribosome and is eliminated

nonsense mediated decay

Question 7

mis-sense variant

Answer 7

single base substitution

changes type of amino acid in protein

may or may not be pathogenic

may be a polymorphism of no functional significance

Question 8

pathogenic variant or polymorphism?

Answer 8

changes amino acid conserved through evolution
disrupts active site or splice site
not common
effect on protein function

Question 9

expansion of a tri-nucleotide repeat

Answer 9

huntington’s disease CAG
myotonic dystrophy CTG
fragile X CGG

Question 10

heterogeneity

Answer 10

one gene one variant one disease

huntingtons

Question 11

allelic heterogeneity

Answer 11

lots of different variants in one gene

Question 12

locus hetergeneity

Answer 12

variants in different genes give same clinical condition

hypertrophic cardiomyopathy

different variants in same gene can give rise to different conditions - genotype/phenotype correlations

Question 13

dominant variants

Answer 13

manifest disease phenotype in heterozygous state

one variant and one normal allele

Question 14

recessive variants

Answer 14

homozygous state
variants in both alleles
majority of pathogenic variants

Question 15

loss of function variants

Answer 15

only one allele functioning. most recessive

haplo-insufficiency

Question 16

gain of function variants

Answer 16

increased gene dosage e.g. PMP22 duplication on 1 allele in hereditary motor and sensory neuropathy type 1A

increased protein activity e.g. variant occurs at recognition site for protein degradation leading to accumulation of undegraded protein within cell

Question 17

dominant-negative variants

Answer 17

protein from variant allele interferes with protein from normal allele

Question 18

genetic test clinical contexts

Answer 18

diagnostic
predictive
carrier
prenatal
preimplantation genetic diagnosis
screening susceptibility

Question 19

diagnostic test

Answer 19

patient has signs and symptoms suggesting a particular diagnosis
molecular genetic test will confirm a diagnosis

Question 20

predictive testing

Answer 20

testing at risk family members for a previously identified familial variant - often dominant

Huntingtons no intervention

BRCA1/2 some intervention

Question 21

carrier testing

Answer 21

autosomal recessive and X-linked disorder

testing individual not helpful - couple testing

reproductive decision making

Question 22

pre-natal test

Answer 22

increased risk of specific condition affecting the fetus

chorionic villous sample or amniocentesis

chromosomal or DNA if specific familial variant has been identified

Question 23

genetic screening

Answer 23

target population, not high risk families

Question 24

susceptibility testing

Answer 24

increased or decreased risk for a multifactorial condition

issue only just emerging