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Neurogenetics Flashcards

1
Q

How many base pairs in the human genome?

A

~3.2 billion

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2
Q

How many genes in the human genomes?

A

~23,000

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3
Q

Does one gene code for only one protein?

A

No - many isoforms

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4
Q

What percentage of DNA encodes proteins?

A

1-2%

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5
Q

What does the rest of DNA that doesn’t code proteins do?

A

We don’t know

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6
Q

What types of mutations (changes in DNA - not necessarily “mutations”) are there?

A 
SNP
single nucleotide variants
Indel
Copy number variants
short tandem repeats
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7
Q

What is a SNP?

A

changes in DNA which don’t cause disease

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8
Q

What is an SNV?

A

“point mutation”, one base substituted by another

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9
Q

What are the types of SNVs?

A

Missense mutation (amino acid change)

Nonsense mutation (generates stop codon)

Splicing mutation (in exon / intron junction) - leads to unstructured protein

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10
Q

What are indels?

A

insertion or deletion of <50 bases

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11
Q

Why are indels bad?

A

Alters mRNA reading frame –> frameshift, unless multiple of 3
The RNA might be degraded if a stop codon is made??

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12
Q

What is a CNV?

A

Gain or loss of >50 bases

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13
Q

How large can a CNV be?

A

a megabase (very large)

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14
Q

TRUE or FALSE? - CNVs only affect one gene

A

FALSE - multiple genes can be affected

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15
Q

When are short tandem repeats bad?

A

If it’s a coding region it’s bad, if it’s non-coding it’s not so bad

Extra copies beyond a threshold can be pathogenic

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16
Q

Give examples of short tandem repeats which cause diseases?

A

Coding: CAG –> glutamine eg Huntington’s

Non- coding: eg C9ORF72 –> ALS and related phenotypes
In non-coding regions it can also cause damage

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17
Q

What is the most common mechanism of Gain-of-function mutations?

A

aggregation

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18
Q

How can mutations cause aggregation? - give examples

A

Protein altered: missense mutations in alpha-synuclein (PD), extra glutamines in huntingtin

Too much of a good thing: SNCA CNVs (extra copies of whole gene)

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19
Q

How do mutations cause loss-of-function mutations?

A

Early stop codon (nonsense mutation or frameshift)

Protein is not functional, or not produced at all (mRNA unstable)

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20
Q

What is are the normal inheritance patterns for gain and loss of function mutations?

A

Dominant –> gain of function

Recessive –> loss of function

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21
Q

what is an exception to the normal inheritance patterns of gain or loss of function mutations?

A

haploinsufficiency - Usually with loss-of-function one gene is enough to stay healthy but if both alleles need to be healthy then you get disease if only one is mutated (dominant inheritance)

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22
Q

Are all neurodegenerative diseases inheritied like HD?

A

No

AD,ALS,PD have only some familial cases

23
Q

What is the difference between eukaryotic and mitochondrial DNA?

A 
Tiny
circular genome 
Numerous copies per cell
They may have differences between diff DNA molecules, diff mitochondria, diff cells, diff tissues (heteroplasmy)
 Inheritance is only maternal
24
Q

How many base pairs in mtDNA?

A

16.5 kb

25
Q

What does mtDNA do?

A

encodes proteins of respiratory chain

26
Q

What kinds of mutations do you find in mtDNA?

A

SNVs or deletions

27
Q

What part of the body is most affected by mtDNA mutations and why?

A

Can affect all body, but neurons sensitive - Due to energy demands

28
Q

What are the easiest cases when you are testing for mutations? - examples

A

testing for a specific mutation
Huntington’s: CAG expansion
A specific mutation in family member eg Parkinson’s or Alzheimer’s gene

29
Q

What are harder cases when testing for mutations?

A

looking for any mutation that may cause this disease

30
Q

What do you use to look for any mutation (not a specific one)?

A

NGS or sanger
Mostly next gen is used bc high throughput. But, Sanger is used for simple genes bc it’s fast and cheap.
You could use a gene panel to look for a group of common mutations

31
Q

What is the disadvantage of just sequencing the exome?

A

what if the mutation is in the non-coding region?

32
Q

What is the problem with the 100,000 genome project?

A
  1. the analysis is really tricky
  2. Ethics: what if you find a mutation which is unconnected to what you are studying? Save someone’s life by telling them or tell them and mess up their life?
33
Q

CNV analysis is easy - TRUE or FALSE?

A

FALSE

34
Q

What kinds of tests are there?

A

Diagnostic
Predictive
Risk alleles

35
Q

give examples of diagnostic tests?

A

Most straightforward eg “do I have Huntington’s?”

Family risks eg “is my PD due to a mutation?” are a bit less straightforward

36
Q

give examples of predictive tests

A

will i get HD? - looking for the CAG expansion

37
Q

what are the problems with predictive tests?

A

Complex… ethics, counseling
Should we test someone who might have a genetic cause of PD, if you’re not sure?
Example: My grandpa had hand tremors before dying of a heart attack at 70 and my dad did too but he never got diagnosed.

Survivors guilt with a negative result

Getting a positive result - psychological issues

38
Q

give examples of risk alleles we can test for

A

Carrying GBA increases risk of PD 5-10x

apoE: number of ε4 alleles influences risk of Alzheimer’s

39
Q

what does GBA encode?

A

glucocerebrosidase

40
Q

what disease does GBA mutation cause and how is it inherited?

A

Causes Gaucher disease (recessive), a lysosomal storage disorder,

If you have 2 mutations, you get Gaucher but if you have 1 your get no disease but your risk of Parkinson’s will increase

41
Q

Is gaucher’s disease a gain or loss of function disease?

A

unclear - Is it because lysosomes don’t work well or because the GBA mutation leads to increased aggregation

42
Q

what are the problems with checking for risk alleles

A

what if you can’t cure the disease

can you explain/understand/quantify risk?

43
Q

Name and discribe patterns of inheritance

A

Autosomal dominant: risk 50% to offspring
autosomal recessive: 25% if both parents carriers
This is why there is inbreeding depression
X-linked (recessive): male only?
Mitochondrial: maternal

44
Q

what are points to remember in clinic when doing genetic tests?

A

Is there a family history?

“censored” : parent died before age of onset

Consanguinity? (same village?) -inbreeding

One condition can result from mutations in different genes

Genes are there nt to cause the disease but to do important things in the body

can get variable phenotype from same gene

what kind of penetrance does the gene have

anticipation

45
Q

name mutations that cause PD, what they code for and their inheritance

A

SNCA - alpha synuclein - dominant

PRKN - Parkin - recessive

PINK1 - PTEN-induced putative kinase1 - recessive

DJ-1 - Protein DJ-1 - recessive

LRRK2 - leucine rich repeat kinase 2 - dominant

46
Q

what is an example of a gene mutation that causes variable phenotypes?

A

C9ORF72 - ALS

47
Q

compare the penetrance of two different PD mutations

A

SNCA mutations: essentially complete (PD)

LRRK2 G2019S: incomplete, ~70% by age 70 (PD)
Penetrance is high but not full

48
Q

Give an example of anticipation

A

HD: More repeats - earlier onset (each generation gets it earlier)

49
Q

TRUE or FALSE? - effect size is high for common mutations

A

FALSE

Effect size is higher for rare alleles and lower for common alleles usually

50
Q

Can Sporadic disorders have a genetic components?

A

YES
Rare cases carry causative Mendelian mutations (~1%)
Dominant: alpha-synuclein (SNCA), LRRK2
Recessive: parkin, DJ1, PINK1

heritability: ~30% (the 29% comes from more common low impact variants)

51
Q

In how many chromosomes (according to GWAS) is there a PD risk allele?

A

all of them

52
Q

What is the use of PD genetics in clinic and how is PD genetics NOT used in clinic?

A

USES:
GBA carriers more likely to get dementia- but you can’t prevent it!
GBA carriers should avoid deep brain stimulation - some people do worse
Predict risk to children

NOT:
confirm diagnosis
NO evidence can target treatment based on mutation presence
GWAS

53
Q

what is the use of genetics in neurology out of clinics? - examples

A

Genetics helps us understand pathogenesis -

PD LLRK2 - maybe involved in vesicular trafficking

ALS - trying to find out why some get ALS and others get other diseases from C9ORF72

HD - showing that repeat size increases through paternal transmission due to instability in the sperm

54
Q

what if you see a genetic disease but can’t find mutations in the blood?

A

You might have a mutation in the brain or another place (somatic mutations) which will not be found in blood

Neuro (23 decks)

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