Genetics and Child Health Flashcards
do the strands of DNA bind in a parallel or anti-parallel form?
anti parallel
how many base pairs are there?
3,000,000,000
how many genes make a human?
30,000
how many polymorphisms do you find on average in a person?
3,000,000
2 general approaches to genetic testing?
array
sequencing
which chromosome looks like a teddy bear?
22
what is array testing?
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
baby born at 38 weeks not feeding floppy wide spaced eyes squashed nose (depressed nasal bridge) large forehead what is the first genetic test?
array comparative genomic hybridisation
what is the most sensitive test?
array
therefore usually the first test done
what does next generation sequencing do?
sequences lots (up to the entire genome) pick out the genes and only analyse the bits you want
what is considered a normal genome?
the commonest form of gene sequence
what are the problems with genome-wide analysis?
data files are big
identification of many many polymorphisms - however only one is causative
date interpretation is complex
how can the cost of next generation sequencing be reduced?
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
how much of the genome do exons make up?
1-2%
what is the NOMAD database?
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
what are the consequences of a mutation in the intron region of a gene?
inotronic variant
low likelihood of effect
what are the consequences of a mutation in the exon region of a gene?
exonic variant potential to: - change amino acid sequence - create a STOP - cause a frameshift - have no effect
how do you know a genetic change causes disease?
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
how can you distinguish a polymorphism from a causative mutation?
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
what are the types of DNA mutation?
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
what is gestalt?
a pattern you recognise
- e.g the pattern of down syndrome (facial features etc) is instantly recognisable
speech delay cleft palate unusual eyes and eyebrows tendency to drool short 2nd phalanges of 5th finger
kabuki makeup syndrome
can present with normal array results but next generation sequencing shows heterozygous MLL2 mutation
where is the mutation in kabuki makeup syndrome?
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
what is a de novo mutation?
not inherited
a new mutation which arises spontaneously in a child
do all de novo mutations cause disease?
no
many de novo mutations in every child, just depends on where the mutation is
what is the best test for de novo paradigm?
next generation sequencing with clinical assessment
what is the main determinant of de novo mutations in a child?
the paternal age
give an example of a genetic disorder which can be treated?
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
what are the consequences of a mutation in the splice junction?
change to splice sequence
usually 1 or 2 bases into intron
causes splicing error
