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~2-3% of children are born with a significant genetic condition
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Cancer genetics : 5% of cancers is due to a higher risk genetic inherited predisposition
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Learning Disability :
Signifcantly reduced ability to understand new or complex information, to learn new
skills
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5% children have a learning disability, affects boys more
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It is a developmental condition present from birth
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What are the causes?

→ Genetic causes
→ Problems during pregnancy and birth :
- Maternal infections
- Teratogens
- Prematurity
- pre/peri/postnatal trauma
→ Incidents after birth :
- Serious illness
- Head injury
- Poor nutrition
- Exposure to toxins
There are a number of different reasons for LD
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Duchenne Dystrophy, some are purely due to
the environment eg
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But most conditions are due to genetic and environmental
factors eg
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Why make a diagosis?
To help understand the aetiology
To discuss genetic aspects of the condition eg
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Monosomy, Trisomy
Translocations :
- Robertsonian
- Reciprocal
Deletions/Duplications
Most common trisomy is trisomie 21
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with a very small p arm (13, 14, 15, 21, 22)
→ can cause trisomies or monosomies
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→ when 2 bits of chr
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Balanced Reciprocal Translocation : if they cause a problem it’s often LD
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Someone with reciprocal translocation can have the following gametes :

In the last 2 gametes, there is additional and deleted genetic information which is what
can cause problems in the foetus
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You can have ​microscopic deletions​ → small deletions that can still be seen on the
karyotype eg
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Common submicroscopic deletion is ​microdeletion of chr22q11= DiGeorge syndrome​
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These deletions are too small to be seen in microscope, so have to use other methods :
Fluorescent In Situ Hybridisation (FISH)​ : molecular probe that attaches to that
particular region of chr 22 and tells us whether or not there is a duplication or deletion
there
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22 so that
you can see the 2 chr
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If you don’t know what the syndrome is, ie
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You compare reference DNA to test DNA → patient sample is labelled with red
fluorescent dye, reference sample is labelled with green fluorescent dye : you then
hybridise them to a slide which has probes specific to chromosome regions on it
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→ eg
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between individuals, some of these variations are just
what makes us unique/different from other people and aren’t pathogenic
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they would not be the cause of the development problem as they are present in
normal people too but in some families there might be some LD associated with them
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Can’t to it with array CGH, we generally
use ​Sanger sequencing​ or ​Next Generation Sequencing ​: panels of genes that
cause a particular phenotype, or whole exome sequencing or whole genome
sequencing
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→ you get a lot of information
which you have to narrow down to what you are actually looking for
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If one parent is affected (and has 1 copy of the gene), there’s a 50:50 chance of having
an affected child
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Tuberous Sclerosis​ : dominant condition, but has a very variable penetrance (ie
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Autosomal recessive
You need 2 faulty copies to be affected
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Often in autosomal conditions there is no family history of the condition, or maybe only
the siblings would be affected (not the parents, grandparents…)
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Eg
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X-linked Recessive
Sex-linked conditions with mutation on X chr
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Can be
very mildly affected due to random X inactivation (we only need one copy of the X chr
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)
There’s a 50% chance for any girl to inherit the affected X and 50% chance for a boy to
inherit the X
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There is no male to
male transmission as men will pass their X chr to a girl only
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Fragile X syndrome​ : accounts for 5% of all males with LD
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Molecular technology to pick this up is a triplet primed PCR test that can
count the number of repeats of a section in a gene
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A number of other conditions are due to triplet repeat expansions, triplet repeat
expansions are :
- unstable/dynamic therefore can increase in size in next generation
- Instability depends on parent of origin eg
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→ some genes are imprinted ie
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In any gametogenesis, the imprint is removed and when the
embryo is formed the imprint is reapplied so not all maternally inherited alleles will be
expressed and vice versa : hence the importance of having both parent’s contribution
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If that impriting goes wrong it can lead to problems eg
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Eg if the embryo lacks the paternal A gene, then there will be an imbalance in the
expression of this gene
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This can also occur due to ​uniparental Disomy​ : during embryogenesis you can have a
trisomic zygote, but then the zygote realises this is wrong so kicks out one of the chr to
have a normal number, but it’s kicked out the paternally inherited gene so now has 2
maternal imprints so has no paternal imprint

Eg
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Due to loss of paternally expressed SNRPN and adjacent genes
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Angelman Syndrome ​: epilepsy, severe learning disability, happy affect
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Other causes of LD are teratogens, ie
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Most common is ​Fetal alcohol syndrome​ : causes autistic features, characteristic
behaviour and facial features, microcephaly…
Also ​Fetal Valproate syndrome​ → seizure medication can cause this : behavioural
difficulties, characteristic facial features

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