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MBChB Year 3 > Week 1 - Genetics > Flashcards

Week 1 - Genetics Flashcards

1
Q

The presence of male breast cancer in a family with other breast cancers, suggests what gene may be mutated

A

BRCA2

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2
Q

Out of MSH2, MLH1, BRCA2, RET and APC- which one is NOT a tumour suppressor gene?

A

RET (proto-oncogene)

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3
Q

Proto-oncogenes do what?

A

They participate in the normal cellular response to growth factors

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4
Q

What 4 capabilities must be acquired for a cell to develop into a cancer?

A
  1. Proliferative signalling
  2. Avoidance of apoptosis
  3. Bypassing replicated senescence
  4. Insensitivity to anti-growth signalling
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5
Q

What do tumour suppressor genes do?

A
  • Normally inhibit progression through the cell cycle

- Promote apoptosis or act as stability genes

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6
Q

What do proto-oncogenes do?

A
  • Normally stimulate the cell cycle

- Activation –> “oncogenes” with gain of function

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7
Q

What do stability genes/caretaker genes do?

A

Minimise genetic alterations

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8
Q

What are the 2 broad types of cancers?

A
  1. Sporadic

2. Familial

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9
Q

Describe Sporadic cancer?

A
  • Common
  • Late onset
  • Single primary tumour
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10
Q

Describe Familial cancer?

A
  • Uncommon
  • Early onset
  • Often multiple primaries
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11
Q

How are most of the more common cancer predisposition syndromes inherited?

A
  • Autosomal dominant fashion

- Mainly due to inheritance of an altered tumour suppressor gene giving inactivation of the wild-type allele

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12
Q

What is the Knudson’s hypothesis 1971?

A

Two hits –> Cancer

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13
Q

List 2 common inherited cancer syndromes?

A
  1. Breast cancer

2. Colon cancer

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14
Q

What 4 things can a cancer family history clinic offer?

A
  1. Family tree then verify diagnosis
  2. Estimate likelihood of predisposing gene mutation
  3. Discuss screening, risk factors, preventative measures
  4. Testing
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15
Q

What are the 2 breast cancer genes which can be tested for mutations?

A
  1. BRCA1

2. BRCA2

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16
Q

What are the 3 less common genes which cause a high-risk of developing familial breast cancer?

A
  1. TP53
  2. PALB2
  3. PTEN
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17
Q

What are 2 questions you should ask during a history if you suspect breast cancer?

A
  1. Presence of ovarian cancer in the family? (BRCA1)

2. Male breast cancer in family? (BRCA2)

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18
Q

There are at least ___ loci that confer an increased susceptibility to breast cancer?

A

72

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19
Q

What does each genetic variant generally confer?

A

A 10-20% increased risk of breast cancer

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20
Q

What is the function of BRCA1 & BRCA2 proteins?

A

DNA repair by homologous recombination of double-strand breaks

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21
Q

When would you do DNA testing in an affected individual?

A
  • If they have at least 10% chance of possessing a mutation in BRCA1 or BRCA2
  • Use of “next generation sequencing”
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22
Q

What are 2 possible preventative measures offered to BRCA1 or BRCA2 mutation carriers?

A
  1. Prophylactic bilateral mastectomies

2. Prophylactic oophorectomies

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23
Q

List the 3 common genes which can be mutated in ovarian cancer?

A
  1. BRCA1
  2. BRCA2
  3. MLH1 / MSH2
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24
Q

What is a possible treatment for ovarian cancer?

A

PARP (poly ADP ribose polymerase) inhibition (olaparib)

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25
Q

Describe colon cancer?

A
  • Mostly autosomal dominant inheritance

- Mostly hereditary non-polyposis colon cancer (2-3%)

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26
Q

What can some colon cancers be?

A

Familial adenomatous polyposis or FAP (0.5%)

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27
Q

Describe Hereditary non-polyposis colon cancer (HNPCC)?

A
  • Usually only a few polyps (<10)

- Uterus, stomach, ovary

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28
Q

What is Hereditary non-polyposis colon cancer (HNPCC) due to?

A

Inheritance of mutation in miss-match repair (MMR) system genes (important for accurate DNA replication)

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29
Q

What is the are the 6 cancers associated with miss-match repair (MMR) gene mutation?

A
  1. Colon cancer
  2. Endometrial cancer
  3. Ovarian cancer
  4. Gastric cancer
  5. Urothelial cancer
  6. Gliomas
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30
Q

How do you screen for those at risk of HNPCC?

A

Colonoscopies

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31
Q

How should you screen individuals at high risk of colon cancer?

A
  • 2 yearly colonoscopies from age 25

- 2 yearly upper GI endoscopy from age 50

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32
Q

What drug reduces the risk of colon cancer according to the CAPP2 trial?

A

Aspirin

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33
Q

What are the 4 genes causing HNPCC & what are their %?

A
  1. MLH1 - 50%
  2. MSH2 - 40%
  3. MSH6 - 7-10%
  4. PMS2 - <5%
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34
Q

What gene is mutated in Familial adenomatous polyposis (FAP)?

A

APC gene

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35
Q

What is a clinical sign in 80% of people with Familial adenomatous polyposis?

A

Congenital hypertrophy of the retinal pigment epithelium (CHRPE)

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36
Q

What is the screening test for familial adenomatous polyposis (FAP)?

A

Annual bowel screening from age 11

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37
Q

What is Li Fraumeni syndrome?

A

Rare autosomal dominant cancer predisposition syndrome (breast cancer, brain tumours, sarcoma, leukaemia, adrenocortical carcinoma)

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38
Q

What are the % chances of cancer in Li Fraumeni syndrome by age 30 and 50?

A
  • 50% by age 30

- 90% by age 50

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39
Q

What gene is mutated in Li Fraumeni syndrome?

A

TP53 (master control gene)

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40
Q

Describe how to understand a pedigree/family tree?

A
  • Roman numerals = generations
  • Male = square
  • Female = circle
  • Diagonal line = dead
  • Young–>Old = Left–>Right
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41
Q

If the mother has a mutated BRCA gene, what are the chances of her daughter inheriting the mutated gene? And what are her chances in developing breast cancer?

A
  • 1 in 2 (50%) chance in inheriting the BRCA gene
  • The general population has a 80% chance of getting breast cancer, however her chance is 50x80% = 40% chance of getting breast cancer
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42
Q

What is an activated proto-oncogene called?

A

Oncogene

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43
Q

What chromosome is the BRCA1 gene on?

A

17

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44
Q

What chromosome is the BRCA2 gene on?

A

13

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45
Q

What does a low-penetrance mean?

A

That you have the gene variant, however, you only have a small increased chance of actually getting the disease

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46
Q

What are the clues to indicate an autosomal dominant inheritance?

A
  • Both males & females
  • Vertical pedigree pattern
  • Variable expression & complete/incomplete penetrance
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47
Q

What are the effects of a mother taking thalidomide for her morning sickness during pregnancy?

A
  • Baby born with limb defects
  • Failed organ development
  • Miscarriages
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48
Q

What are 3 other examples of autosomal dominant conditions?

A
  • Inherited breast or colon cancer
  • Autosomal dominant polycystic kidney disease (ADPKD)
  • NF1 (neurofibromatosis type 1)
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49
Q

Describe Sickle cell disease

A
  • Autosomal recessive

- Sickle-shaped red blood cells in a sickle haemoglobin (HbS) homozygote

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50
Q

What are clues to indicate an autosomal recessive inheritance?

A
  • Usually horizontal pattern
  • Both males & females
  • Expressivity more constant within a family
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51
Q

Give 4 examples of autosomal recessive conditions?

A
  1. Cystic fibrosis
  2. Phenylketonuria (PKU)
  3. Spinal muscular atrophy (SMA)
  4. Congenital adrenal hyperplasia
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52
Q

A man affected by an autosomal recessive condition has a partner affected by the same condition. They have 3 children. What is the chance that their 3rd child will be affected?

A

100% as the parents are both affected and not just carriers

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53
Q

Autosomal dominant diseases are expressed in ________?

A

Heterozygotes

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54
Q

Autosomal recessive diseases are expressed in _________ OR _________?

A
  • Homozygotes (2 identical mutated alleles)
    OR
  • Compound heterozygotes (CPD) (2 different mutations)
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55
Q

What does Mendelian inheritance mean?

A

Its to do with a single gene

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56
Q

How can you tell the difference between a X linked condition and an autosomal dominant condition?

A
  • X linked: More common in males as they only have 1 X chromosome, whereas females have 2. But a father could not pass on the gene to his son as he passes on the Y chromosome
  • Autosomal dominant: Father passes gene onto son (X gene not affected). Both male and females can be affected
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57
Q

What are 2 examples of how some people can be more likely to develop a disease than others?

A
  1. Environmental factors (switch on and off genes ie. epigenetic)
  2. Other modifier genes
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58
Q

What does variable expression mean regarding genetic inheritance?

A

Some people are more affected by the disease than others even though they both inherit the same gene mutation

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59
Q

What does incomplete penetrance mean?

A

You could inherit the gene (increasing the risk), however not actually develop the disease/condition

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60
Q

What does complete penetrance mean?

A

You inherit the gene and have a 100% risk of developing the disease/condition

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61
Q

Give an example of a disease which is autosomal dominant with complete penetrance?

A

Achondroplasia

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62
Q

How does thalidomide work?

A

It’s a teratogen which changes how the protein functions but doesn’t alter the DNA sequence

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63
Q

Give an example of a modifier gene in breast cancer?

A

FGFR2 variants in BRCA2 mutation carriers

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64
Q

What is the % chance of being a carrier for an autosomal recessive gene if both parents are carriers?

A

50%

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65
Q

What is the % chance of NOT being affected/ being a carrier for an autosomal recessive gene if both parents are carriers?

A

25%

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66
Q

For autosomal dominant the offspring of affected individuals usually have a _____ risk?

A

50:50

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67
Q

For autosomal recessive the offspring of affected individuals have a ____ risk?

A

Low

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68
Q

What are “obligate carriers”?

A
  • Individuals who are clinically unaffected but carry a gene mutation based on analysis of the family history
  • Usually applies to disorders inherited autosomal recessive & X-linked recessive
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69
Q

Describe X linked recessive inheritance?

A
  • No male to male transmission
  • Mostly or only males affected
  • Occasionally “manifesting carriers” due to “skewed X-inactivation”
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70
Q

What is skewed X-inactivation?

A

Occurs when the inactivation of 1 X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated

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71
Q

What are the risks for an X linked recessive carrier (heterozygote) mother having male & female children?

A
  • MALE: 50% affected

- FEMALE: 50% carriers

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72
Q

What are the risks for an X linked recessive affected father having male & female children?

A
  • MALE: none affected

- FEMALE: 100% carriers

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73
Q

Give 3 examples of X-linked dominant inheritance?

A
  1. Vitamin D resistant rickets
  2. Incontinentia pigmenti (male lethality)
  3. Rett syndrome (male lethality)
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74
Q

Describe the pattern of X-linked dominant inheritance?

A

Like autosomal dominant but NO male transmission

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75
Q

What is the sex ratio for X-linked recessive inheritance?

A

Male&raquo_space; Female

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76
Q

What is the sex ratio for X-linked dominant inheritance?

A

F:M = 2:1

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77
Q

What is the pedigree pattern for X-linked recessive inheritance?

A

Knight’s move (“L” shaped movement)

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78
Q

What is the pedigree pattern for X-linked dominant inheritance?

A

Vertical

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79
Q

Describe Genetic “anticipation”?

A

Increasing severity & earlier age of onset in successive generations

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80
Q

Give 3 examples of diseases with atypical mendelian inheritance?

A
  1. Huntington disease
  2. Fragile X syndrome
  3. Myotonic dystrophy
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81
Q

Describe pseudo-dominant inheritance?

A
  • It’s an autosomal recessive condition with a very high carrier frequency
  • It appears like autosomal dominant
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82
Q

Give an example of a condition with pseudo-dominant inheritance?

A

Gilbert syndrome

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83
Q

Describe Gilberts syndrome?

A
  • Carrier frequency: ~50%

- Intermittent jaundice due to unconjugated hyperbilirubinaemia

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84
Q

Describe mitochondria DNA?

A
  • Smaller genome
  • Circular
  • 37 genes
  • No introns
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85
Q

Describe mitochondrial inheritance?

A
  • Inherited only from the mother
  • All children inherit it from the mother but to variable extents
  • Syndromes often affect muscle, brain & eyes
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86
Q

Give an example of a disease with mitochondrial inheritance?

A

Leigh’s disease

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87
Q

What are the 4 examples of atypical inheritance?

A
  1. Genetic anticipation
  2. Gonadal mosaicism
  3. Pseudodominant
  4. Mitochondrial
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88
Q

Describe the presentation of Huntington’s disease?

A
  • Onset between 30-50

- Progressive chorea, dementia & psychiatric symptoms

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89
Q

What is chorea?

A

Involuntary movements

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90
Q

Describe the genetics behind huntington’s disease?

A
  • Autosomal dominant with genetic anticipation
  • Unstable length
  • Mutation in gene huntingtin (HTT) on chromosome 4
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91
Q

Upto how many CAG repeats would you be unaffected by Huntington’s?

92
Q

What is huntington’s disease prone to genetically?

A

Expansion during meiosis esp. from father

93
Q

What happens if there are 36-39 CAG repeats in Huntington disease?

A

Incomplete penetrance (not affected)

94
Q

What unit is repeated in Huntington’s disease?

95
Q

What does CAG encode?

A

Polyglutamine tract

96
Q

List 2 things that an expansion of the polyglutamine tract in Huntington’s disease cause?

A
  1. Insoluble protein aggregates

2. Neurotoxicity

97
Q

Describe the tests available for Huntington’s disease?

A
  • DNA testing
  • No cure
  • Test unaffected relatives
  • Presymptomatic test
98
Q

How many CAG repeats leads to someone being symptomatic with Huntington’s disease?

99
Q

What inheritance class is myotonic dystrophy?

A

Autosomal dominant with genetic anticipation

100
Q

List the signs and symptoms of myotonic dystrophy?

A
  • Progressive muscle weakness in early adulthood
  • Myotonia
  • Cataracts
101
Q

Describe the genetic basis of myotonic dystrophy?

A

Unstable length mutation of CTG repeat

102
Q

How many CTG repeats are needed to be affected by myotonic dystrophy?

A

50 or more

103
Q

There is a higher chance of expansion when myotonic dystrophy mutation is transmitted by ______?

104
Q

There is a higher chance of expansion when huntington’s mutation is transmitted by ______?

105
Q

How does an abnormal DMPK mRNA in myotonic dystrophy cause myotonia?

A

Indirect toxic effect upon splicing of other genes ie. the chloride ion channel CLCN1 gene

106
Q

What genetic inheritance is cystic fibrosis?

A

Autosomal recessive

107
Q

What is the carrier frequency for cystic fibrosis?

A

1 in 20 –> 1 in 25

108
Q

What are 2 clinical problems caused by cystic fibrosis?

A
  1. Recurrent lung infections

2. Exocrine pancreatic insufficiency (85-90% of cases)

109
Q

How do you screen for cystic fibrosis?

A

Screening newborns by immunoreactive trypsin (IRT) levels

110
Q

How do you confirm diagnosis of cystic fibrosis?

A

DNA testing (cystic fibrosis mutations) &/OR sweat testing (increased chloride concentration)

111
Q

What gene is mutated in cystic fibrosis?

112
Q

Describe the pathogenic mechanism of cystic fibrosis?

A
  • Defective chloride ion channel

- Increased thickness of secretions

113
Q

What is the most common mutation on CFTR gene?

A

F508del (deletion of a phenylalanine at position 508)

114
Q

What is cascade screening?

A

Identification of mutations permits prenatal diagnosis if desired & the subsequent identification of carrier relative

115
Q

Describe the symptoms/signs of neurofibromatosis type 1 (NF1)?

A
  • Cafe au lait macules
  • Neurofibromas
  • Short stature
  • Macrocephaly
  • Learning difficulties in 30% (severe in 3%)
116
Q

Neurofibromatosis type 1 (NF1) has very ____ expressivity?

117
Q

List 4 things that people with NF1 are at increased risk of?

A
  1. Hypertension
  2. Scoliosis requiring surgery
  3. Pathological tibial fractures
  4. Tumours
118
Q

List the 3 significant tumours that NF1 gives an increased risk of?

A
  1. Phaeochromocytomas
  2. Sarcomas
  3. Optic pathway gliomas
119
Q

What do people with NF1 need?

A

Annual follow-up

120
Q

What type of genetic inheritance is Duchenne & Becker Muscular dystrophy?

A

X-linked recessive

121
Q

Where is the location of the DMD (duchenne muscular dystrophy) gene?

A

Xp21 (largest human gene)

122
Q

What does dystrophin form?

A

A link between F-actin intracellularly & the dystroglycan complex

123
Q

What do boys with Duchenne Muscular Dystrophy have an increased level of?

A

Serum creatine kinase (SCK) from birth

124
Q

How does the serum creatine kinase increase in Duchenne Muscular Dystrophy?

A

Creatine kinase leaks out of damaged muscle fibres into serum into blood

125
Q

What is the onset of Duchennes muscular dystrophy?

126
Q

What is the main effects of duchenne muscular dystrophy compared to becker muscular dystrophy?

A
  • DMD: Wheelchair by ~12yrs

- BMD: Wheelchair much later, or not at all

127
Q

What is the genetic inheritance of fragile X syndrome?

A

X-linked recessive with genetic anticipation due to repeats in the 5’ UTR region of FMR1 gene

128
Q

What is fragile X syndrome the most common INHERITED cause of?

A

Significant learning disability

129
Q

What are the normal karyotypes in males and females?

A
  • MALE: 46, XY

- FEMALE: 46, XX

130
Q

What is Trisomy 21?

A

Common type of down syndrome

131
Q

What is the risk of parents having a 2nd child when they already have a child with translocation down syndrome?

132
Q

Describe the clinical signs of down syndrome?

A
  • Learning difficulites
  • Most can talk & walk and some can read & write
  • Heart malformations
  • Hypothyroidism
  • Single palmar crease
133
Q

What is another name for Edwards syndrome?

A

Trisomy 18

134
Q

Describe the signs/symptoms of Edwards syndrome?

A
  • Small chin
  • Clenched hands with overlapping fingers
  • Malformations of heart, kidney & other organs
135
Q

What can individuals with edwards syndrome have if they survive the 1st year?

A

Profound learning difficulties

136
Q

What is another name for Patau syndrome?

A

Trisomy 13

137
Q

What is a usual problem for people with Patau syndrome?

A

Congenital heart disease

138
Q

What % of people with Patae syndrome die within 1 month?

139
Q

List the clinical signs/symptoms of Patau syndrome?

A
  • Cleft lip & palate
  • Microphthalmia
  • Abnormal ears
  • Clenched fists
  • Post-axial polydactyly
140
Q

How do trisomies usual arise?

A

From maternal non-dysfunction (failure of normal separation of the 2 chromosomes number 21, 18 or 13) in meiosis

141
Q

What are trisomies more frequent with?

A

Increased Maternal Age

142
Q

What can translocation chromosomal problems account for?

A

Multiple miscarriages or stillbirths in a family

143
Q

What would you ask when assessing a patients genetics?

A
  • Patient clinical history: age of onset of symptoms? Progression?
  • Family History: consanguinity? miscarriages? stillbirths?
  • Examination: any dysmorphic features, normal growth (height, occipital-frontal circumference)
144
Q

What are the 9 places you would assess for dysmorphic features in a patient?

A
  1. Head shape & size (macro- or micro-cephaly)
  2. Eyes
  3. Ears
  4. Nose (size, nares)
  5. Philtrum (smooth)
  6. Mouth (size, lips, teeth)
  7. Limbs (disproportion)
  8. Skin (lumps, abnormal pigmentation)
  9. Hands and feet
145
Q

What would you specifically look for around the eyes when assessing for dysmorphic features?

A
  • Palpebral fissures (size, slant)

- Spacing (hypertelorism)

146
Q

What is Hypertelorism?

A

Pupils too far apart

147
Q

What would you specifically look for around the ears when assessing for dysmorphic features?

A
  • Size, shape, position (low-set)

- Rotation of the top ear anteriorly/posteriorly

148
Q

When could someone have a thin upper lip?

A

Fetal alcohol syndrome

149
Q

What would you specifically look for around the hands & feet when assessing for dysmorphic features?

A
  • Palmar creases

- Fingers & toes (correct number, polydactyly, syndactyly)

150
Q

What can be 2 clinical signs of Velocardiofacial syndrome?

A
  1. Prominent nose

2. Up-slanting palpebral fissures

151
Q

What chromosome is deleted in Velocardiofacial syndrome?

152
Q

What can be 3 clinical signs of Rubinstein Taybi syndrome?

A
  1. Downslanting palpebral fissures
  2. Microcephaly
  3. Broad thumbs & big toes
153
Q

What chromosome is deleted in Rubinstein Taybi syndrome?

A

16 (short arm)

154
Q

What is pre-implantation genetic diagnosis (PGD)?

A
  • 1 or 2 cells removed for testing at 3days when embryo contains 6-10 cells
  • Analyse the cells through PCR (look at DNA directly or neighbouring DNA markers) or FISH (look at particular parts of the chromosome)
155
Q

What are the 2 PROS of pre-implantation genetic diagnosis (PGD)?

A
  1. Permits implantation of unaffected embryos

2. Termination of pregnancy is unnecessary

156
Q

What are the 4 CONS of pre-implantation genetic diagnosis (PGD)?

A
  1. Long wait
  2. Not available to all women
  3. Difficulty with multiple visits & procedures
  4. “Take home baby rate” usually <50% per cycle
157
Q

What are the 3 stages in life that genetic screening tests are offered?

A
  1. Pregnancy
  2. Neonatal
  3. Adulthood
158
Q

What are the 6 main principles of a screening programme?

A
  1. Should be clearly defined disorder
  2. Appreciable frequency
  3. Advantage to early diagnosis
  4. Few false positives (specificity)
  5. Few false negatives (sensitivity)
  6. Benefits outweigh the risks
159
Q

What is the sensitivity equation?

A

TP/(TP+TN)

  • TP= true positive
  • TN= true negative
160
Q

What is the specificity equation?

A

TN/(TN+FP)

  • TN= true negative
  • FP= false positive
161
Q

Describe how to do a neonatal screening test

A

Guthrie card blood spot from the heel of a baby

162
Q

What are the 2 conditions which can be detected during neonatal screening by mass spectrometry?

A
  1. Phenylketonuria

2. MCADD

163
Q

What are 2 different diseases which can be screened postnatally?

A
  1. Tay Sachs disease screening for Jewish people (pre-pregnancy)
  2. Thalassaemia population carrier screening for thalassaemia
164
Q

For pre-implantation diagnosis under what circumstances would you transfer the embryos to mother?

A
  • Transfer only unaffected embryos

- Up to 2 embryos

165
Q

What pre-implantation genetic diagnostic test can tell embryo sexing for X-linked recessive conditions?

166
Q

List 4 facts regarding genetic counselling?

A
  1. Provides genetics-related advice & info
  2. Advice should be non-directive
  3. Info regarding investigation & interpretation
  4. Thinking about implications for relatives
167
Q

Describe CUBS in detecting Down Syndrome (combined ultrasound and biochemical screening)?

A
  • Maternal blood biochemical markers

- Ultrasound: nuchal translucency increases in down syndrome

168
Q

What are the 2 conditions which can be detected during neonatal screening by immuno-assay?

A
  1. Congenital hypothyroidism

2. Cystic fibrosis

169
Q

What is the condition which can be detected during neonatal screening by High Performance Liquid Chromatography (HPLC)?

A

Sickle Cell disorder

170
Q

Give 3 examples of neonatal screening tests?

A
  1. Mass spectrometry
  2. Immuno-assay
  3. High Performance Liquid Chromatography (HPLC)
171
Q

What are 3 situations when genetic diagnostic tests would be appropriate?

A
  1. Individuals with high genetic risk
  2. Need high sensitivity & specificity
  3. Done after ie. positive screening test or if there is a family history
172
Q

Give 2 examples of prenatal diagnostic tests?

A
  1. Chorionic villous sampling

2. Amniocentesis

173
Q

When can Chorionic villous sampling occur in pregnancy?

A

10-12 weeks

174
Q

When can Amniocentesis occur in pregnancy?

A

16-18 weeks

175
Q

What is the miscarriage rate for Chorionic villous sampling?

A

Up to 1/50

176
Q

What is the miscarriage rate for Amniocentesis?

A

Up to 1/100

177
Q

When do you get results back from Chorionic villous sampling?

178
Q

When do you get results back from Amniocentesis?

179
Q

What are the 3 future developments for genetic diagnostic tests?

A
  1. Array comparative genomic hybridization (aCGH)
  2. Non-invasive prenatal diagnosis (NIPD)
  3. Non-Invasive Prenatal Testing (NIPT) using next generation sequencing (NGS)
180
Q

When would you use Array comparative genomic hybridization (aCGH)?

A

For foetuses with abnormal ultrasound scans

181
Q

When would you use Non-invasive prenatal diagnosis (NIPD)?

A
  • Achondroplasia

- Fetal sex determination

182
Q

When would you use Non-Invasive Prenatal Testing (NIPT)?

A

Aneuploidy (Down syndrome)

183
Q

What is genomics?

A
  • Concerns all the DNA

- Nuclear (3 billion base pairs) & mitochondrial (17000 base pairs) genomes

184
Q

What are 3 DNA-based detection methods?

A
  1. Detection of point mutations
  2. Detection of sub-microscopic duplications & deletions
  3. Rapid detection of aneuploidies
185
Q

What are the 2 ways that DNA sequencing can detect point mutations?

A
  1. Automated fluorescent dideoxy (Sanger) sequencing 1 gene at a time
  2. Massively parallel (“next-generation”) sequencing many or all genes
186
Q

What are the 2 ways of detecting sub-microscopic duplications & deletions?

A
  1. MLPA (PCR-based)

2. Array comparative genomic hybridisation (aCGH)

187
Q

What does Array comparative genomic hybridisation (aCGH) do?

A
  • Looks across all the chromosomes at once

- Looks for changes in the colour of millions of spots (yellow= normal, green/red= abnormal)

188
Q

What is an Aneuploidy?

A

Abnormal number of chromosomes, that is not a multiple of 23 ie. trisomy 18

189
Q

What is a way to rapidly detect aneuploidy?

A

Quantitative fluorescent PCR (QF-PCR)

190
Q

Describe Quantitative fluorescent PCR (QF-PCR)?

A
  • Specific aneuploidies & rapid
  • Use markers on chromosomes 21, 13, 18 to give you PCR peaks on the output
  • If you see 2 signals then that means its ok but if there are 3 signals then that means the child probably has an extra chromosome (trisomy)
191
Q

What are the 2 chromosome-based analysis methods?

A
  1. Karyotyping

2. FISH

192
Q

What does FISH stand for?

A

Fluorescence in-situ hybridisation

193
Q

Describe what FISH shows in Williams syndrome?

A

Deletion of elastin gene on 1 chromosome 7

194
Q

Describe Karyotyping?

A
  • Light microscopy

- Resolution about 4-5Mb

195
Q

What 4 things can you analyse with next generation sequencing?

A
  1. Single gene (Sanger sequencing)
  2. Several genes at once (“gene panel”)
  3. Exome (all the protein coding regions of all the genes)
  4. Genome (entire genome)
196
Q

What are the 2 types of DNA sequencing?

A
  1. Sanger (fluorescent dideoxynucleotide) sequencing

2. Next generation (or massively parallel) sequencing

197
Q

What is the most common method for next generation sequencing?

A

Illumina method

198
Q

Describe the illumina method for next generation sequencing?

A
  • Take image
  • Fluorescence present where any base has been added
  • Add one nucleotide/ Take image again
  • Sequence is constructed by the computer
199
Q

What is exome gene testing?

A

Analyses all the genes

200
Q

What is non-invasive prenatal testing/diagnosis (NIPT/NIPD) testing?

A

Maternal plasma, free fetal DNA

201
Q

What 3 things can non-invasive prenatal testing/diagnosis (NIPT/NIPD) be used for?

A
  1. Fetal sex determination (X linked conditions)
  2. Paternal mutations (FGFR3 mutation)
  3. Testing for aneuploidy
202
Q

What is the future development for next generation sequencing?

A

Sequencing of whole exomes/ whole genomes

203
Q

In precision medicine what can the treatment be tailored to?

A

Specific disease-causing mutation (inherited mutation), in tumour cell (somatically acquired)

204
Q

What disease is Ivacaftor used for?

A

Cystic fibrosis

205
Q

Describe how Ivacaftor is used to treat cystic fibrosis?

A

It reopens the CFTR chloride ion channel which therefore goes onto help the lungs

206
Q

What is the 3rd most common cystic fibrosis mutation?

A

G551D (present in 4% of patients)

207
Q

What do the majority of non-small cell lung cancer patients present with?

A

Inoperable/metastatic disease

208
Q

Give an example of a new targeted therapy for non-small cell lung cancer?

A

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

209
Q

What is the gene mutation often found in breast cancer?

A

HER2 (human EGFR2)

210
Q

What is the drug useful if there are too many copies of HER2 in breast cancer?

A

Trastuzumab (Herceptin)

211
Q

What are the 2 possible future therapies for Duchenne muscular dystrophy?

A
  1. Exon skipping

2. Drug to permit read-through of premature stop codons (Ataluren or PTC124)

212
Q

Describe how exon skipping therapy can help with duchennes muscular dystrophy?

A

Convert duchennes muscular dystrophy to BMD phenotype by altering splicing patterns to correct the reading from with antisense oligonucleotides

213
Q

Describe gene editing with CRISPR-CAS9 system?

A
  • CRISPR is a guide RNA that finds the target sequence

- Increased specificity recently with double nickase system

214
Q

What is base editing?

A

Converting a G back to an A for example

215
Q

What is a liquid biopsy?

A

Blood test looking for the tumours DNA mutation pattern

216
Q

Would 2 different gene mutations located on the same copy of a gene lead to someone getting the disease?

217
Q

Could a female be affected by an X-linked disorder if she had a mutation on both of her X chromosomes?

218
Q

A boy has cystic fibrosis. What is the approx % chance of his mother’s brother being a carrier?

A

50% because CF is autosomal recessive both the boys parents are carriers, the mother must have inherited the mutation from her parents. If it was the grandfather, that means that the mother’s brother has a 50% chance of inheriting it from him. If it was the grandmother, the brother has a 50% chance of inheriting it. Therefore either grandparent means that the mother’s brother has a 50% chance of being a carrier

219
Q

A boy has cystic fibrosis. What is the approx chance that his healthy older sister is a carrier.

220
Q

What is a sub-microscopic gene?

A

One not able to be seen through a microscope (<4 million base pairs)

221
Q

What is QF-PCR used most often in the diagnostic lab?

A

Trisomy of 21, 18 or 13 (rapid method)

222
Q

What can ARMS be commonly used for?

A

Single nucleotide substitution in a KNOWN position in a gene

223
Q

What condition does NOT show genetic anticipation?

224
Q

Describe why familial cancers with a mutated tumour suppressor genes are autosomal dominant and not recessive?

A
  • Dominant family tree ie. the tumour predisposition & single tumour suppressor gene that is inherited
  • In the tumour cells there will be 2 hits but not the inheritance of mutation from both parents like in autosomal recessive
225
Q

Could a man carry a BRCA1 or BRCA2 gene mutation?

A

YES as a carrier & has a 50% chance of passing it on

226
Q

What 2 genes do proto-oncogenes include?

A
  1. MYC gene

2. FOS gene

227
Q

What does DNA polymerase do?

A

Replication

MBChB Year 3 (15 decks)

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