Genetics and Child Health

Question 1

do the strands of DNA bind in a parallel or anti-parallel form?

Answer 1

anti parallel

Question 2

how many base pairs are there?

Answer 2

3,000,000,000

Question 3

how many genes make a human?

Answer 3

30,000

Question 4

how many polymorphisms do you find on average in a person?

Answer 4

3,000,000

Question 5

2 general approaches to genetic testing?

Answer 5

array

sequencing

Question 6

which chromosome looks like a teddy bear?

Answer 6

22

Question 7

what is array testing?

Answer 7

allows you to look for sub-microscopic deletions or duplications of chromosome material across the whole genome
only detects imbalanced chromosome rearrangements
at each point that you test, is there more or less DNA in the person?
- half as much DNA = deletion
- 2X more DNA = duplication

Question 8

baby born at 38 weeks
not feeding 
floppy
wide spaced eyes
squashed nose (depressed nasal bridge)
large forehead
what is the first genetic test?

Answer 8

array comparative genomic hybridisation

Question 9

what is the most sensitive test?

Answer 9

array

therefore usually the first test done

Question 10

what does next generation sequencing do?

Answer 10

sequences lots (up to the entire genome)
pick out the genes and only analyse the bits you want

Question 11

what is considered a normal genome?

Answer 11

the commonest form of gene sequence

Question 12

what are the problems with genome-wide analysis?

Answer 12

data files are big
identification of many many polymorphisms - however only one is causative
date interpretation is complex

Question 13

how can the cost of next generation sequencing be reduced?

Answer 13

only sequencing the exons in the genome as these are the only parts which code for anything and covers most of what we can interpret

Question 14

how much of the genome do exons make up?

Answer 14

1-2%

Question 15

what is the NOMAD database?

Answer 15

database of polymorphisms in the population
if a polymorphism is found in a patient - can check the database and if its present in a lot of the population = less likely to cause disease

Question 16

what are the consequences of a mutation in the intron region of a gene?

Answer 16

inotronic variant

low likelihood of effect

Question 17

what are the consequences of a mutation in the exon region of a gene?

Answer 17

exonic variant
potential to:
- change amino acid sequence
- create a STOP
- cause a frameshift
- have no effect

Question 18

how do you know a genetic change causes disease?

Answer 18

it is in a gene that matches the phenotype
it has an effect on gene function
it is not listed as a polymorphism in NOMAD
it is in evolutionary conserved bit of gene
it is de-novo in chil - if only the child is affected
OR
it is present in other affected family members

Question 19

how can you distinguish a polymorphism from a causative mutation?

Answer 19

if the geetic change is only present in the affected child = causative mutation
if change present in affected child and unaffected parent = probably just a polymorphism

Question 20

what are the types of DNA mutation?

Answer 20

wild type = normal
premature stop = early stop codon
missence = one base is different
insertion = extra base inserted into the sequence - everything pushed along one space
deletion (out of frame) = deletion of a number of bases not divisible by 3 (1, 2 or 4 etc bases)
deletion (in frame) = deletion of a number of bases divisible by 3 (i.e a codon) 
Triplet expansion = duplication of a codon

Question 21

what is gestalt?

Answer 21

a pattern you recognise

- e.g the pattern of down syndrome (facial features etc) is instantly recognisable

Question 22

speech delay
cleft palate
unusual eyes and eyebrows
tendency to drool
short 2nd phalanges of 5th finger

Answer 22

kabuki makeup syndrome

can present with normal array results but next generation sequencing shows heterozygous MLL2 mutation

Question 23

where is the mutation in kabuki makeup syndrome?

Answer 23

splice junction of MLL2 gene
therefore exon cant be spliced from intron and the either the mRNA degrades before translation or non-functional protein is made

Question 24

what is a de novo mutation?

Answer 24

not inherited

a new mutation which arises spontaneously in a child

Question 25

do all de novo mutations cause disease?

Answer 25

no

many de novo mutations in every child, just depends on where the mutation is

Question 26

what is the best test for de novo paradigm?

Answer 26

next generation sequencing with clinical assessment

Question 27

what is the main determinant of de novo mutations in a child?

Answer 27

the paternal age

Question 28

give an example of a genetic disorder which can be treated?

Answer 28

spinomuscular atrophy
- can be treated at an early age with treatments which improve gene splicing
tuberous sclerosis
- can be managed with rapamycin which targets mTor signalling

Question 29

what are the consequences of a mutation in the splice junction?

Answer 29

change to splice sequence
usually 1 or 2 bases into intron
causes splicing error