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Year 2 EMS GiM > Genetics in Medicine > Flashcards

Genetics in Medicine Flashcards

1
Q

Give 5 reasons for a clinical genetics referral?

A

1) Affected patient for investigation or diagnosis
2) Family history of a genetic disorder or condition with a genetic component
3) Fetal loss/abnormality
4) Recurrent miscarriages
5) Strong family history of cancer

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2
Q

What is the purpose of genetic counselling?

A

1) To inform

2) To talk about choices ie. whether to have tests or more children

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3
Q

What are the 3 stages involved in making a genetic diagnosis?

A

1) Family tree
2) Physical examination
3) Genetic tests

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4
Q

What defines the boundaries of synthesis in PCR?

A

Oligonucleotides (primers)

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5
Q

What is the rough process of PCR?

A

1) Heat denaturation - 94 degrees
2) Primer annealing - 55 degrees
3) Primer extension - 72 degrees
Then repeat

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6
Q

How can PCR be used to determine an allele with a deletion?

A

Simply separating the products by size using gel electrophoresis to identify those with a deletion ie. smaller
Can identify single deleted base and shows homozygotes, heterozygotes and normal genes

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7
Q

A deletion of nucleotide 35 (guanine) in the connexin 26 gene is the most common cause of what?

A

Most common inherited cause of deafness

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8
Q

Using what kind of assay is allele specific mutation detection carried out and what is its application?

A

Oligonucleotide ligation assay

Used to distinguish between a known disease causing point mutation and the normal allele

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9
Q

How does an oligonucleotide ligation assay work? not the process just a general overview

A

1) Allele specific oligos (primers) are synthesised so that their 3’ end nucleotides base pair with the changed nucleotide to identify normal and mutant alleles that differ by one base pair
2) The reaction will not take place when the 3’ end is not perfectly base paired thus identifying the presence or absence of a particular allele that that oligo is specific for

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10
Q

What is the process of an oligonucleotide ligation assay?

A

1) Have 1 assay for each specific oligo (one that identifies normal and those that identify mutants)
2) The specific oligo along with a shared primer that will anneal to both the mutant and normal allele
3) If the oligo anneals completely to the sample (ie specifically the 3’nucleotide) then ligation can take place between the specific oligo and the shared primer, if the allele doesnt match the primer this cannot happen
4) Ligated and unligated products can then be identified using gel electrophoresis thus identifying the absence or presence of a specific allele

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11
Q

Other than DNA testing what other test is involved in the Leeds Method of Management algorithm for CF testing?

A

IRT (immunoreactive trypsin)

IRT - DNA - IRT

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12
Q

What are the limitation of the CF Genotyping assay?

A

It will only identify the 32 mutations for which it has been designed, there may be other CF-causing mutations that are not identified by this assay

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13
Q

Give 3 examples of templates which may be unsuitable for use in PCR and what is the alternative to PCR in these cases?

A

1) Gene may be too big for PCR
2) Fragile X mutation in FMR1 gene is a repetitive tract of (CGG)n sequence
3) GC-rich regions are difficult to PCR
Southern blotting technique is used as an alternative, old technique but still important for diagnostic work

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14
Q

What ‘discovery’ method is used in unknown mutations and what are the 2 types?

A

Sequencing

1) Sanger/traditional sequencing (using chain termination chemistry)
2) Clonal/next generation sequencing

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15
Q

What is the rough principle behind clonal sequencing?

A

Sample of DNA is cut into fragments, grown on a slide in dense clusters (to make the fluorescent signal stronger) , each kind of nucleotide is fluorescently labelled and these are added along with primers, as each new nucleotide is added a laser is used to activate the fluorescence and a computer reads which nucleotide has been added in each cluster thus reading the sequence

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16
Q

What is the advantage of next generation clonal sequencing over traditional sequencing?

A

Faster and cheaper

Can just sequence exons due to knowing the introns/exons from the human genome project

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17
Q

What is Cadasil?

A

Caused by a single gene, is a genetic predisposition to stroke

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18
Q

What is the definition of a multifactorial/complex genetic disorder?

A

Caused by the interaction of multiple genes in combination with environmental factors eg. type 2 diabetes, IHD

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19
Q

What is the definition of single gene/mendelian genetic disorder?

A

A mutation in a single gene, eg. CF

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20
Q

What is the definition of a chromosomal genetic disorder?

A

An imbalance or rearrangement in chromosome structure eg. aneuploidy, deletion, translocation

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21
Q

What is the definition of a mitochondrial genetic disorder?

A

Caused by a mutation in mitochondrial DNA

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22
Q

What is a somatic mutation?

A

Mutation within a gene in a defined population of cells that results in disease eg. cancer

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23
Q

Autosomal dominant inheritance normally affects what in the body?

A

1) Structural proteins
2) Receptors
3) Transcription factors

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24
Q

What is the definition of penetrance?

A

The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage. Can alter with age, ie by 80 years of age Huntingtons disease has 100% penetrance

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25
Q

What is meant by incomplete penetrance? Give an example

A

Not all relatives who inherit the mutation develop the disorder eg. BRCA1 mutation

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26
Q

What is the definition of expressivity?

A

Variation in expression - the extent to which a heritable trait is manifested by an individual. Ie. in Marfan syndrome, some people will have aortic dilatation, some lens dislocation and some stretch marks

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27
Q

What is the definition of anticipation?

A

The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases, there is an increase in the severity of symptoms too

28
Q

What 2 genetic diseases does anticipation occur in?

A

1) Myotonic dystrophy

2) Huntington’s disease

29
Q

What is the definition of a new dominant or de novo mutation?

A

a new mutation that has occurred during gametogenesis or in early embryonic development - the child is the first to be affected in the family but can now pass the mutation on to their own children

30
Q

Name 3 disorders with autosomal recessive inheritance

A

1) Cystic fibrosis
2) Hemochromatosis
3) Sickle cell disease

31
Q

Why can you not have male to male transmission in X linked inheritance?

A

Males do not pass on an X chromosome to male offspring thus impossible to pass on the mutation

32
Q

Are females affected in X linked inheritance?

A

Females can be unaffected or mildly through to severely affected

33
Q

Who is usually more severely affected in X linked inheritance, males or females?

A

Males

34
Q

Name 4 genetic conditions passed on by X linked inheritance?

A

1) Duchenne muscular dystrophy
2) Fragile X syndrome
3) Red/green colour blindness
4) Haemophilia

35
Q

What is fragile X syndrome?

A

Caused by constriction near the end of the long arm of an x chromosome that leads to breakage or deletion
Second only to downs syndrome as a cause of mental defect
Affected men have an IQ below 50 and are prone to violent outbursts, about 1/3 of females who inherit the mutation are also mentally retarded

36
Q

What is X inactivation/ lyonisation?

A

The process of random inactivation of one of the X chromosomes in cells with 2 or more X chromosomes
Happens routinely in all cells
Compensates for the presence of the double X gene dose
Once inactivated the x chromosome remains inactive throughout the lifetime of the cell and all its descendants, most but not all of the genes are switched off on the inactivated X

37
Q

At what stage in development does x inactivation occur?

A

Early embryogenesis

38
Q

In females and X linked inheritance, due to X inactivation approx. 50% of cells express the normal gene, what 2 processes can affect this expression?

A

1) Skewed X inactivation - random preference for the normal X chromosome to be switched off resulting in a significant phenotype
2) Tissue variability - random preference for the X chromosome with the mutation to be active in crucial tissue group eg. Muscle in Duchenne muscular dystrophy

39
Q

Name 2 X linked dominant conditions, what is the difference in expression in males and females?

A

1) Rett syndrome - lethal in males, phenotype only in females
2) Fragile X syndrome - females are asymptomatic due to fully symptomatic depending on X inactivation pattern

40
Q

Name 3 X linked recessive conditions, what is the general expression of these in females?

A

1) Red-green colour blindness
2) Haemophilia
3) Duchenne muscular dystrophy
carrier girls are usually unaffected but can have significant symptoms due to x inactivation, girls are fully affected if they inherit a mutation from mum and dad

41
Q

Why can a condition with mitochondrial inheritance not be passed from father to offspring?

A

The sperm does not have any mitochondria, all mitochondria comes from the mother

42
Q

How many genes are there within mitochondrial DNA?

A

27

43
Q

How do you show males and females in a pedigree?

A

Circle - females

Square - males

44
Q

How are affected people identified in a family pedigree?

A

Symbol is shaded in

45
Q

How is a deceased person identified in a family pedigree?

A

Line through their symbol

46
Q

How is a therapeutic abortion showed in a family pedigree?

A

Triangle with a line through it

47
Q

How is a spontaneous abortion (miscarriage) shown in a family pedigree?

A

Triangle with no line through it

48
Q

How is a still born baby of unknown sex shown in a family pedigree?

A

Diamond with a line through it

49
Q

What is consanguinity and by how much does it increase the risk of a congenital birth defect and why?

A

Couples who are blood relatives
Potentially share recessive gene mutations
Risk of congenital birth defect 5-6% (2-3% in general population if no family history of genetic condition)
Seen in all ethnic groups

50
Q

How is a pregnancy of unknown sex shown in a family pedigree?

A

Diamond with a P written in it, EDD is shown instead of DOB

51
Q

How is a consanguineous couple depicted in a family pedigree?

A

By a double line

52
Q

How are twins (identical and non identical) depicted in a family pedigree?

A

2 lines coming from one point with a line between to show where twins are identical

53
Q

What is meant by the term genetically heterogeneous?

A

Single phenotype can be caused by any one of a number of allele mutation

54
Q

Early onset AD has been shown to be genetically heterogeneous, what does this mean?

A

Shows family clustering

Different genes may be involved in different families but give similar end stage symptoms

55
Q

Which 2 main alleles have been shown to be implicated in early onset AD and why?

A

PSEN1 and PSEN2
encode a protein with gamma secretase activity responsible for cleavage of beta plaque from APP
Can also be caused by mis sense mutations in APP

56
Q

Specific alleles of the gene for which protein are implicated in earlier onset of Alzheimer’s disease?

A

APOE - also implicated in heart disease

57
Q

What are the 3 haplotypes of APOE?

A

1) E2
2) E3
3) E4

58
Q

Which haplotypes of APOE confers an increased susceptibility to AD, which has a protective effect?

A

E4 haplotype confers increase in susceptibility
E2 haplotype has a protective effect
E4/E4 homozygotes are affected much earlier than heterozygotes E2/E3

59
Q

Age related macular degeneration is one of the simplest multifactorial conditions, which 2 genes have major effects (there are some with minor effects) and which environmental factor has a major effect and which an intermediate effect?

A

Genetic major effects: CFH, ARMS2
Major environmental effect: Smoking
Intermediate environmental effect: Light exposure

60
Q

Does screening for susceptibility alleles in multifactorial disease confirm disease?

A

No!

61
Q

What are the 4 main examples of polygenic disease?

A

1) Schizophrenia
2) AD
3) Type 2 DM
4) Age related macular dystrophy

62
Q

What is age related macular dystrophy characterised by?

A

Early deposition of drusen

63
Q

What is a haplotype?

A

Group of genes within an organism that was inherited from a single parent

64
Q

What 2 factors may modify the penetrance of a gene?

A

1) Other genetic variations

2) Environmental factors

65
Q

What are the 3 categories of ‘cancer genes’ and their functions?

A

1) Gatekeepers - monitor and controls cell division and death, preventing accumulation of mutations
2) Caretakers - Improve genomic stability eg. repair of mutations
3) Landscapers - control the surrounding stromal environment - not actually a mutation in the cell that becomes malignant but a mutation in the cells that make up its environment

66
Q

In terms of inherited cancer genes do the 3 types all have the same penetrance?

A

No a mutated gatekeeper gene tends to have higher penetrance that a mutated caretaker which in turn has a higher penetrance than a landscaper gene

Year 2 EMS GiM (6 decks)

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