Dit document bevat alle 10 lessen van het keuzevak Neurogenetics, met de laatste 5 lessen 'Disease focus'. Elke les is uitgeschreven naar de woorden van de prof en hoort samen bij de gegeven powerpoints. De titels van de dia's zijn geschreven in het document als titeltjes met een streep onder.
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Neurogenetics
Exam: written exam with part multiple choice and open questions.
28/02
Neurological disorders
Classification system
These are all valid ways to define the diseases
No good or bad way to do classification but helps to keep track for all the diseases discussed
here
Movement disorders
Parkinson disease is the most common of these
Many others and they are all caused by the defected cerebellum
o Can have diseases with a too fast or a too slow movement
o Hypokinetic = too slow, hyperkinetic = too fast
Ataxia
o Has different types, where people have difficulties with moving and speaking
o Some are genetic and others can happen by alcohol or for example gluten intolerance
o Can cause heart problems, is different within every person
o Took over a decade to diagnose
Dementias
Frontotemporal and Prion see next classes
Diseases of the white matter
Myelin is normally formed and afterwards distructed
It is formed from the beginning as a problem, or destructed later (like in MS)
Multiple sclerosis
Neuromuscular disorders
the upper and the lower
ALS is an example of this
o Is a deadly disease that affects the motor nerve cells
o People become independent on others for help
o Frontotemporal dementia can happen same time with ALS
Paroxysmal disorders
These occur unexpectedly and in episodes
Neurodevelopmental disorders
Things like fragile X
Neurocutaneous disorders
Neurofibromatosis type 1 (NF1)
Tuber sclerosis complex
1
, These tumors are in the brain and these cause epilepsy, they do not die but have other
effects and disabilities
Cerebrovascular diseases
Genetic form of the disease is known as CADASIL
o Causes a lot of blood vessels in the brain
Major adult psychiatric disorders
Factors suggesting a neurogenetic disorders
How to recognize if it is genetic?
o If it is inside a family
It can be genetic but not in a family and vice versa
o Neurologists have combinations of symptoms for certain diseases and certain genetic
factors can be the sign of a disorder
o Subtle onset with a chronic, progressive cause
o Consanguinity
When the parents are related to one another
o Increased frequency in a certain ethnic group
Why would somebody have multiple individuals with the disorder in the family but is not
genetic?
o Environmental factors
o Age (Alzheimer for example because also common disease) = sporadic cases
o It can skip a generation, can be because there is a recessive gene
Genetic but not in the family?
o De novo mutations
o Early death in the family
o Non paternity
When the dad is not the dad
Inheritance patterns
Examples
o First one is recessive because the parents are not affected
o Second example is dominant
You expect 50% to be affected, here not the case because lot of people have
died already
o Third example is recessive because the parents are not affected
You only see males that are affected (so might be X-linked)
Most patients/families affected by neurological disorders
Not everyone that has the mutations presents symptoms = reduced penetrance
A disease may not always be mono genetic but mutations can come together and you might
need 2 mutations or more to have a disorder and thus have a disease
From monogenic to complex diseases
If you add more genes oligogenic or complex where multiple genes play a role
A single disorder can present in many different ways
2
, o The same disease can need one, or 2 or more genes
The more genes come together, the more different the phenotypes get of the person
o Every time there is a slightly different phenotype, whilst the different persons have
the same disease
o Is because different genes that play a role in the disease
Impact of gene discovery
Gene identification methods
Linkage analysis
o Based on the sharing of pieces of DNA between persons, measured by a LOD score
o You use STR markers, need 400-1000 markers for the genome
o You find a locus and do sequencing analysis in that reason, to find the gene that has
the mutation
o The challenge is that you need large families to do this
o Phenocopies and reduced penetrance will mess up the analysis
Phenocopy is somebody who has the exact same phenotype as everyone else
in the family but does not carry the gene
Population genetics
o Use unaffected individuals
A person that is unrelated and a control needed
o Have to be careful that the cases and the control are well matched
o When people did association studies, people would take one gene at a time
Did work sometimes
o Genome-wide association study
The standard now for common variants in the population to use
Manhattan plot are the different chromosomes and every dot is a different
variant
The higher the variant, the more significant the p-value
P < 5x10^-8
o Needed to say it is significantly associated with the disease
Anything above the line means this variant is a risk factor for the
disease
Polygenic risk scores
o You need the effect size
o Apply information to an individual and calculate the persons risk
So information from the population that you apply on individual level
Exam!
You need a large population to come up with the effect size of a specific
variant and then you pull the variants together
You take a single individual one at a time and then calculates its
personal risk score
Based on that individuals data but with the effect size of the
population
o Considerations
You have to decide which variants to include
Burden analysis
3
, Let’s say you look for blue variants
We should group all coding variants in gene X
All loss-of-function variants in gene X
it shows if you choose carefully and combine them in a burden analysis, you can also find rare
variants
o common variants GWAS
common vs rare
in burden analysis the variants have a weaker effect like risk factors
common variants with GWA
common variants with strong effects are different to identify
need to be able to place the studies in the wright part of the figure for the exam
example of ALS (Amyotrophic lateral sclerosis)
many different genes can be present
familial
o SOD1
o ALS2
o C9orf72 (see later)
More than 20 different genes known, found in families and in sporadic individuals
Oligogenic basis of ALS
o Often families where there is reduced penetrance, oligogenic disease and phenotypic
heterogeneity
They often come together in the families
Gene x Environmental interaction in ALS
o Interaction between genetics and environments, also in ALS
ALS risk genes identified through GWAS
o 15 different risk loci found
Polygenic risk score
o Overlap between the risk for ALS and the risk for schizophrenia is shown
Exome sequencing study in ALS
o Type of analysis if we want to go beyond families = Burden analysis is done here
Mutations affecting the coding sequence
A gene can be coding in one sequence but not in another, there are multiple transcripts and
can have different effects
Nonsense-mediated decay
Is an mRNA surveillance mechanism
If a mutation is introduced before the stop codon, better to get rid of the entire transcript
Exon junctions complexes that are usually around the exons
By the premature stop, degradation is triggered because the exon junction complexes are still
sitting there
However when there is a mutation in the last exon or 55nt before, NMD does not work and
the exon junctions stay
o This can play a role in neurologic diseases
4
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