Genetic Disorders (chromosomal/DNA mutations) Flashcards Preview

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Flashcards in Genetic Disorders (chromosomal/DNA mutations) Deck (47)
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1
Q

What is a copy number variation in a chromosome?

A

is duplication or deletion of a considerable amount of DNA (E.g. a gene) meaning there is variation in the chromosome that then goes onto meiosis. e.g. CAG repeat in Huntington’s.

2
Q

If a woman was having repeated miscarriages, what kind of translocations (balanced/unbalanced) would you expect to see for her and the foetus?

A

Balanced or normal - for her as unaffected

Unbalanced for foetus as this has more risk

3
Q

What is the difference between trisomy/triploidy? Are they compatible with life?

A

Trisomy is 3 of one chromosome e.g. 21 - yes Downs Syndrome. Triploidy is 3 copies of every chromosome not compatible with life. 15% of all miscarriages are this, and term babies die shortly after birth.

4
Q

Would you use aCGH in a neonate with a heart abnormality and why?

A

Yes as copy number variations are one reason for congenital cardiac problems - so look for unbalanced translocations.

5
Q

Would you use aCGH in a child with developmental delays/autism and why?

A

Yes because learning difficulties/developmental delay can be caused by unbalanced translocations.

6
Q

Would you use aCGH in recurrent miscarriages and why? What would you use instead?

A

No you don’t use it pre-term and mother will be either balanced or normal so won’t be detected. Use FISH on mother - can see balanced and unbalanced - for known aneuploidies - need to know what you’re looking for as probe specific.

7
Q

Would you use aCGH for sperm and egg donors and why?

A

Yes to check if there are unbalanced translocations that would not be compatible with life. Also some translocations (e.g. Roberstonian) can cause aneuploidies (trisomies etc) that may not be compatible with life.

8
Q

If you have an ‘apparently balanced’ de Novo translocation in a developmentally delayed child would you use aCGH and why?

A

Yes because its de Novo it may not actually be balanced. You can use aCGH to see if it is unbalanced.

9
Q

What is a substitution that results in purine to purine swap or pyrimidine to pyrimidine swap?

A

Transition

10
Q

What is a substitution that results in a change from purine to pyrimidine or pyrimidine to purine?

A

Transversion

11
Q

Mutation that results in a change in gene product is called ________

A

Missense

12
Q

A mutation that results in the change of polypeptide length could be two things what are they?

A

Stop codon (nonsense), frameshift resulting in early/late stop codon.

13
Q

What is a mutation called when it doesn’t have an effect on protein?

A

Silent

14
Q

What are transposable elements and give 3 consequences of TEs on genes

A

Jumping genes - specific DNA sequences that have no fixed abode on chromosomes but jump around randomly.

1) Can jump to non coding region - nothing
2) Can jump into gene (more likely if bigger) and inactivate
3) Can jump onto promotor sequence and activate transcription.

15
Q

Inversions of chromosomes can occur after what DNA damage repair defect?

A

Error in NHEJ

16
Q

Error in splicing due to mutations in introns can lead to what in terms of protein made? How?

A

Change length of protein (as introns left in)

Change amount of protein (as change mRNA - may become non function and degrades)

17
Q

Would there be an effect if a whole codon is deleted from DNA? is this a frameshift?

A

No not frameshift as triplet code deleted - this may or may not have an effect on protein.

18
Q

Give an example of how can insertion occur (what can be inserted)?

A

Transposable elements

19
Q

How can translocation of a gene in a somatic cell cause cancer? How does this occur in Leukemia?

A

DSB - translocation where ABL on chrome 9 goes to chrome 22 and fuses with BCR gene - new gene formed on chrome 22 = Philadelphia chromosome. Codes for protein that is constantly on = cell prolif & cancer

20
Q

If asked how to detect a mutation that is 1-10Mb (e.g. 10,000,000 bp) which level of test would you be thinking (DNA, gene, protein, chromosome)?

A

This is chromosome level

21
Q

Does RNA poly proofread?

A

No - erros in protein more common but protein and RNA molecule easily degraded by cell.

22
Q

Are RNAs inherited? What if the consequence of this if you have a faulty RNA?

A

No - so won’t pass on faulty RNA to next generation.

23
Q

If a child has an autosomal dominant disorder but neither parent is affected, what can you assume?

A

The mutation causing the disease is spontaneous.

24
Q

Is it likely for spontaneous mutations to cause autosomal recessive diseases? Why?

How about a spontaneous mutation to cause the person to be a carrier? Can you think of a disease example?

A

V rare as would have to mutate on both alleles spontaneously.

1 in 25 randomly mutate the CFTR gene so would become carriers.

25
Q

What type of testing could you do to look at chromosome cause of Leukaemia? What is the name of the mutated chromosome that can cause Leukemia and how is this kind of chromosome formed?

A

Cytogenetics - look at FISH - balanced translocation chromosome 9 gene ABL - chromosome 22 BCR - fusion of gene = Philadelphia gene

26
Q

Where in meiosis can Reciprocal translocations occur? How do you assess the possible risk of a reciprocal translocation on a gamete? What are the possible segregation outcomes?

A

Meiosis I

Assess segregation:
Alternate - normal or balanced

Adj 1 - unbalanced most common

Adj 2 - rare and v unbalanced

See if abnormality is known to assess risk - most abnormalities are family specific and may not be known.

27
Q

Name a reciprocal translocation that more commonly occurs?

A

t11:22 - Emanuels Syndrome

11 and 22 have region of DNA more likely to break

28
Q

What is the most common Robertsonion Translocation? What is the chromosome count in a balanced carrier?

A

13:14

45

29
Q

How do Robertsonian translocations occur? Whats the risk at gametogenesis? Whats the risk at pregnancy?

A

Acrocentric chromosomes fuse -

Forms trivalent at meiosis - not stable
Risk of aneuploidy

Homologous carriers can’t have a normal pregnancy

30
Q

If a mum was a homologous carrier for 21:21 Robertsonian translocation what would happen to her children?

A

Likely all be Downs Syndrome

31
Q

What could you use centromere probes in FISH for?

A

To look at copy number analysis - fluorescently label for a particular chromosome’s centromere e.g. to detect isochromosomes

32
Q

What could you use chromosome paints in FISH for?

A

Apply paints to clearly see rearrangements - balanced/unbalanced in FISH

33
Q

What could you use to detect a chromosome micro deletion e.g. in Di George?

A

Use locus specific probe to detect deletion on chromosome 22 when compared to normal labelled chromosome 22.

34
Q

When might you use Kreatch Prenat screen probes with FISH? How do you extract the cells to test?

A

Looking for prenatal aneuploidies e.g Down’s Syndrome - on interphase nuclei only. Use amniocentesis or chorionic villus sampling. Can see whether a pregnancy is affected by an aneuploidy.

35
Q

When could you use aCGH? Which cohort of patients may you use this in?

A

Deletion or duplication

Developmental Delay cohort

36
Q

What is ISCA? What cohort of patients would you use it in? What is a downside compared to karyotyping?

A

Microarray - whole genome at high resolution - can test for known developmental disorders.
V expensive

37
Q

What is UPD uniparental disomy?

A

Homologous chromosomes from one parent

38
Q

What are the four types of UPD?

A

Isodisomy - identical chromosomes from one parent
Heterodisomy - homologous chromosomes from one parent
Segmental UPD - only part of chromosome involved
Acquired UPD - solid tumours/leukaemias

39
Q

Why does UPD matter?

A

Imprinting

40
Q

What is imprinting? Is it bad?

A

Epigenetics leading to silencing of either mother or father allele of a gene. Can be part of normal inheritance, can be bad in disease.

41
Q

How can imprinting lead to disease in UPD? Give a disease example

A

As certain genes are imprinted meaning they are turned off. If you inherit 2 chromosomes from your mother for example and some of those genes are imprinted, you don’t have the fathers chromosome to compensate so there will be no expression of that gene e.g. Prader Willi syndrome chromosome 15

42
Q

When would UPD have no phenotypic effect?

A

If there is no imprinting

43
Q

By what mechanisms can UPD be created (4)? What is a feature of how UPDs are created?

A

Trisomy rescue
Monosomy rescue
Gamete complementation
Mitotic error

All are the result of two separate abnormal events

44
Q

What is gamete complementation?

A

Where both parents gametes are abnormal, one contributes 2 chromosomes and the other none.

45
Q

Future of Prenatal testing?

A

Non invasive e.g. free DNA in placenta/mother blood. Coming soon for Downs syndrome

46
Q

What is the future for sickle cell treatment?

A

Gene editing

Foetal Hb kept switched one

47
Q

What is the future for Huntingtons disease treatment?

A

Find a gene when deleted prevents HD. Inhibit protein Y. Inhibit Kynurenine pathway