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
2
Q
Out of MSH2, MLH1, BRCA2, RET and APC- which one is NOT a tumour suppressor gene?
A
RET (proto-oncogene)
3
Q
Proto-oncogenes do what?
A
They participate in the normal cellular response to growth factors
4
Q
What 4 capabilities must be acquired for a cell to develop into a cancer?
A
- Proliferative signalling
- Avoidance of apoptosis
- Bypassing replicated senescence
- Insensitivity to anti-growth signalling
5
Q
What do tumour suppressor genes do?
A
- Normally inhibit progression through the cell cycle
- Promote apoptosis or act as stability genes
6
Q
What do proto-oncogenes do?
A
- Normally stimulate the cell cycle
- Activation –> “oncogenes” with gain of function
7
Q
What do stability genes/caretaker genes do?
A
Minimise genetic alterations
8
Q
What are the 2 broad types of cancers?
A
- Sporadic
2. Familial
9
Q
Describe Sporadic cancer?
A
- Common
- Late onset
- Single primary tumour
10
Q
Describe Familial cancer?
A
- Uncommon
- Early onset
- Often multiple primaries
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
12
Q
What is the Knudson’s hypothesis 1971?
A
Two hits –> Cancer
13
Q
List 2 common inherited cancer syndromes?
A
- Breast cancer
2. Colon cancer
14
Q
What 4 things can a cancer family history clinic offer?
A
- Family tree then verify diagnosis
- Estimate likelihood of predisposing gene mutation
- Discuss screening, risk factors, preventative measures
- Testing
15
Q
What are the 2 breast cancer genes which can be tested for mutations?
A
- BRCA1
2. BRCA2
16
Q
What are the 3 less common genes which cause a high-risk of developing familial breast cancer?
A
- TP53
- PALB2
- PTEN
17
Q
What are 2 questions you should ask during a history if you suspect breast cancer?
A
- Presence of ovarian cancer in the family? (BRCA1)
2. Male breast cancer in family? (BRCA2)
18
Q
There are at least ___ loci that confer an increased susceptibility to breast cancer?
A
72
19
Q
What does each genetic variant generally confer?
A
A 10-20% increased risk of breast cancer
20
Q
What is the function of BRCA1 & BRCA2 proteins?
A
DNA repair by homologous recombination of double-strand breaks
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”
22
Q
What are 2 possible preventative measures offered to BRCA1 or BRCA2 mutation carriers?
A
- Prophylactic bilateral mastectomies
2. Prophylactic oophorectomies
23
Q
List the 3 common genes which can be mutated in ovarian cancer?
A
- BRCA1
- BRCA2
- MLH1 / MSH2
24
Q
What is a possible treatment for ovarian cancer?
A
PARP (poly ADP ribose polymerase) inhibition (olaparib)
25
Describe colon cancer?
- Mostly autosomal dominant inheritance
| - Mostly hereditary non-polyposis colon cancer (2-3%)
26
What can some colon cancers be?
Familial adenomatous polyposis or FAP (0.5%)
27
Describe Hereditary non-polyposis colon cancer (HNPCC)?
- Usually only a few polyps (<10)
| - Uterus, stomach, ovary
28
What is Hereditary non-polyposis colon cancer (HNPCC) due to?
Inheritance of mutation in miss-match repair (MMR) system genes (important for accurate DNA replication)
29
What is the are the 6 cancers associated with miss-match repair (MMR) gene mutation?
1. Colon cancer
2. Endometrial cancer
3. Ovarian cancer
4. Gastric cancer
5. Urothelial cancer
6. Gliomas
30
How do you screen for those at risk of HNPCC?
Colonoscopies
31
How should you screen individuals at high risk of colon cancer?
- 2 yearly colonoscopies from age 25
| - 2 yearly upper GI endoscopy from age 50
32
What drug reduces the risk of colon cancer according to the CAPP2 trial?
Aspirin
33
What are the 4 genes causing HNPCC & what are their %?
1. MLH1 - 50%
2. MSH2 - 40%
3. MSH6 - 7-10%
4. PMS2 - <5%
34
What gene is mutated in Familial adenomatous polyposis (FAP)?
APC gene
35
What is a clinical sign in 80% of people with Familial adenomatous polyposis?
Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
36
What is the screening test for familial adenomatous polyposis (FAP)?
Annual bowel screening from age 11
37
What is Li Fraumeni syndrome?
Rare autosomal dominant cancer predisposition syndrome (breast cancer, brain tumours, sarcoma, leukaemia, adrenocortical carcinoma)
38
What are the % chances of cancer in Li Fraumeni syndrome by age 30 and 50?
- 50% by age 30
| - 90% by age 50
39
What gene is mutated in Li Fraumeni syndrome?
TP53 (master control gene)
40
Describe how to understand a pedigree/family tree?
- Roman numerals = generations
- Male = square
- Female = circle
- Diagonal line = dead
- Young-->Old = Left-->Right
41
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?
- 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
42
What is an activated proto-oncogene called?
Oncogene
43
What chromosome is the BRCA1 gene on?
17
44
What chromosome is the BRCA2 gene on?
13
45
What does a low-penetrance mean?
That you have the gene variant, however, you only have a small increased chance of actually getting the disease
46
What are the clues to indicate an autosomal dominant inheritance?
- Both males & females
- Vertical pedigree pattern
- Variable expression & complete/incomplete penetrance
47
What are the effects of a mother taking thalidomide for her morning sickness during pregnancy?
- Baby born with limb defects
- Failed organ development
- Miscarriages
48
What are 3 other examples of autosomal dominant conditions?
- Inherited breast or colon cancer
- Autosomal dominant polycystic kidney disease (ADPKD)
- NF1 (neurofibromatosis type 1)
49
Describe Sickle cell disease
- Autosomal recessive
| - Sickle-shaped red blood cells in a sickle haemoglobin (HbS) homozygote
50
What are clues to indicate an autosomal recessive inheritance?
- Usually horizontal pattern
- Both males & females
- Expressivity more constant within a family
51
Give 4 examples of autosomal recessive conditions?
1. Cystic fibrosis
2. Phenylketonuria (PKU)
3. Spinal muscular atrophy (SMA)
4. Congenital adrenal hyperplasia
52
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?
100% as the parents are both affected and not just carriers
53
Autosomal dominant diseases are expressed in ________?
Heterozygotes
54
Autosomal recessive diseases are expressed in _________ OR _________?
- Homozygotes (2 identical mutated alleles)
OR
- Compound heterozygotes (CPD) (2 different mutations)
55
What does Mendelian inheritance mean?
Its to do with a single gene
56
How can you tell the difference between a X linked condition and an autosomal dominant condition?
- 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
57
What are 2 examples of how some people can be more likely to develop a disease than others?
1. Environmental factors (switch on and off genes ie. epigenetic)
2. Other modifier genes
58
What does variable expression mean regarding genetic inheritance?
Some people are more affected by the disease than others even though they both inherit the same gene mutation
59
What does incomplete penetrance mean?
You could inherit the gene (increasing the risk), however not actually develop the disease/condition
60
What does complete penetrance mean?
You inherit the gene and have a 100% risk of developing the disease/condition
61
Give an example of a disease which is autosomal dominant with complete penetrance?
Achondroplasia
62
How does thalidomide work?
It's a teratogen which changes how the protein functions but doesn't alter the DNA sequence
63
Give an example of a modifier gene in breast cancer?
FGFR2 variants in BRCA2 mutation carriers
64
What is the % chance of being a carrier for an autosomal recessive gene if both parents are carriers?
50%
65
What is the % chance of NOT being affected/ being a carrier for an autosomal recessive gene if both parents are carriers?
25%
66
For autosomal dominant the offspring of affected individuals usually have a _____ risk?
50:50
67
For autosomal recessive the offspring of affected individuals have a ____ risk?
Low
68
What are "obligate carriers"?
- 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
69
Describe X linked recessive inheritance?
- No male to male transmission
- Mostly or only males affected
- Occasionally "manifesting carriers" due to "skewed X-inactivation"
70
What is skewed X-inactivation?
Occurs when the inactivation of 1 X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated
71
What are the risks for an X linked recessive carrier (heterozygote) mother having male & female children?
- MALE: 50% affected
| - FEMALE: 50% carriers
72
What are the risks for an X linked recessive affected father having male & female children?
- MALE: none affected
| - FEMALE: 100% carriers
73
Give 3 examples of X-linked dominant inheritance?
1. Vitamin D resistant rickets
2. Incontinentia pigmenti (male lethality)
3. Rett syndrome (male lethality)
74
Describe the pattern of X-linked dominant inheritance?
Like autosomal dominant but NO male transmission
75
What is the sex ratio for X-linked recessive inheritance?
Male >> Female
76
What is the sex ratio for X-linked dominant inheritance?
F:M = 2:1
77
What is the pedigree pattern for X-linked recessive inheritance?
Knight's move ("L" shaped movement)
78
What is the pedigree pattern for X-linked dominant inheritance?
Vertical
79
Describe Genetic "anticipation"?
Increasing severity & earlier age of onset in successive generations
80
Give 3 examples of diseases with atypical mendelian inheritance?
1. Huntington disease
2. Fragile X syndrome
3. Myotonic dystrophy
81
Describe pseudo-dominant inheritance?
- It's an autosomal recessive condition with a very high carrier frequency
- It appears like autosomal dominant
82
Give an example of a condition with pseudo-dominant inheritance?
Gilbert syndrome
83
Describe Gilberts syndrome?
- Carrier frequency: ~50%
| - Intermittent jaundice due to unconjugated hyperbilirubinaemia
84
Describe mitochondria DNA?
- Smaller genome
- Circular
- 37 genes
- No introns
85
Describe mitochondrial inheritance?
- Inherited only from the mother
- All children inherit it from the mother but to variable extents
- Syndromes often affect muscle, brain & eyes
86
Give an example of a disease with mitochondrial inheritance?
Leigh's disease
87
What are the 4 examples of atypical inheritance?
1. Genetic anticipation
2. Gonadal mosaicism
3. Pseudodominant
4. Mitochondrial
88
Describe the presentation of Huntington's disease?
- Onset between 30-50
| - Progressive chorea, dementia & psychiatric symptoms
89
What is chorea?
Involuntary movements
90
Describe the genetics behind huntington's disease?
- Autosomal dominant with genetic anticipation
- Unstable length
- Mutation in gene huntingtin (HTT) on chromosome 4
91
Upto how many CAG repeats would you be unaffected by Huntington's?
35
92
What is huntington's disease prone to genetically?
Expansion during meiosis esp. from father
93
What happens if there are 36-39 CAG repeats in Huntington disease?
Incomplete penetrance (not affected)
94
What unit is repeated in Huntington's disease?
CAG
95
What does CAG encode?
Polyglutamine tract
96
List 2 things that an expansion of the polyglutamine tract in Huntington's disease cause?
1. Insoluble protein aggregates
| 2. Neurotoxicity
97
Describe the tests available for Huntington's disease?
- DNA testing
- No cure
- Test unaffected relatives
- Presymptomatic test
98
How many CAG repeats leads to someone being symptomatic with Huntington's disease?
40
99
What inheritance class is myotonic dystrophy?
Autosomal dominant with genetic anticipation
100
List the signs and symptoms of myotonic dystrophy?
- Progressive muscle weakness in early adulthood
- Myotonia
- Cataracts
101
Describe the genetic basis of myotonic dystrophy?
Unstable length mutation of CTG repeat
102
How many CTG repeats are needed to be affected by myotonic dystrophy?
50 or more
103
There is a higher chance of expansion when myotonic dystrophy mutation is transmitted by ______?
Females
104
There is a higher chance of expansion when huntington's mutation is transmitted by ______?
Males
105
How does an abnormal DMPK mRNA in myotonic dystrophy cause myotonia?
Indirect toxic effect upon splicing of other genes ie. the chloride ion channel CLCN1 gene
106
What genetic inheritance is cystic fibrosis?
Autosomal recessive
107
What is the carrier frequency for cystic fibrosis?
1 in 20 --> 1 in 25
108
What are 2 clinical problems caused by cystic fibrosis?
1. Recurrent lung infections
| 2. Exocrine pancreatic insufficiency (85-90% of cases)
109
How do you screen for cystic fibrosis?
Screening newborns by immunoreactive trypsin (IRT) levels
110
How do you confirm diagnosis of cystic fibrosis?
DNA testing (cystic fibrosis mutations) &/OR sweat testing (increased chloride concentration)
111
What gene is mutated in cystic fibrosis?
CFTR
112
Describe the pathogenic mechanism of cystic fibrosis?
- Defective chloride ion channel
| - Increased thickness of secretions
113
What is the most common mutation on CFTR gene?
F508del (deletion of a phenylalanine at position 508)
114
What is cascade screening?
Identification of mutations permits prenatal diagnosis if desired & the subsequent identification of carrier relative
115
Describe the symptoms/signs of neurofibromatosis type 1 (NF1)?
- Cafe au lait macules
- Neurofibromas
- Short stature
- Macrocephaly
- Learning difficulties in 30% (severe in 3%)
116
Neurofibromatosis type 1 (NF1) has very ____ expressivity?
Variable
117
List 4 things that people with NF1 are at increased risk of?
1. Hypertension
2. Scoliosis requiring surgery
3. Pathological tibial fractures
4. Tumours
118
List the 3 significant tumours that NF1 gives an increased risk of?
1. Phaeochromocytomas
2. Sarcomas
3. Optic pathway gliomas
119
What do people with NF1 need?
Annual follow-up
120
What type of genetic inheritance is Duchenne & Becker Muscular dystrophy?
X-linked recessive
121
Where is the location of the DMD (duchenne muscular dystrophy) gene?
Xp21 (largest human gene)
122
What does dystrophin form?
A link between F-actin intracellularly & the dystroglycan complex
123
What do boys with Duchenne Muscular Dystrophy have an increased level of?
Serum creatine kinase (SCK) from birth
124
How does the serum creatine kinase increase in Duchenne Muscular Dystrophy?
Creatine kinase leaks out of damaged muscle fibres into serum into blood
125
What is the onset of Duchennes muscular dystrophy?
~3yrs
126
What is the main effects of duchenne muscular dystrophy compared to becker muscular dystrophy?
- DMD: Wheelchair by ~12yrs
| - BMD: Wheelchair much later, or not at all
127
What is the genetic inheritance of fragile X syndrome?
X-linked recessive with genetic anticipation due to repeats in the 5' UTR region of FMR1 gene
128
What is fragile X syndrome the most common INHERITED cause of?
Significant learning disability
129
What are the normal karyotypes in males and females?
- MALE: 46, XY
| - FEMALE: 46, XX
130
What is Trisomy 21?
Common type of down syndrome
131
What is the risk of parents having a 2nd child when they already have a child with translocation down syndrome?
High risk
132
Describe the clinical signs of down syndrome?
- Learning difficulites
- Most can talk & walk and some can read & write
- Heart malformations
- Hypothyroidism
- Single palmar crease
133
What is another name for Edwards syndrome?
Trisomy 18
134
Describe the signs/symptoms of Edwards syndrome?
- Small chin
- Clenched hands with overlapping fingers
- Malformations of heart, kidney & other organs
135
What can individuals with edwards syndrome have if they survive the 1st year?
Profound learning difficulties
136
What is another name for Patau syndrome?
Trisomy 13
137
What is a usual problem for people with Patau syndrome?
Congenital heart disease
138
What % of people with Patae syndrome die within 1 month?
50%
139
List the clinical signs/symptoms of Patau syndrome?
- Cleft lip & palate
- Microphthalmia
- Abnormal ears
- Clenched fists
- Post-axial polydactyly
140
How do trisomies usual arise?
From maternal non-dysfunction (failure of normal separation of the 2 chromosomes number 21, 18 or 13) in meiosis
141
What are trisomies more frequent with?
Increased Maternal Age
142
What can translocation chromosomal problems account for?
Multiple miscarriages or stillbirths in a family
143
What would you ask when assessing a patients genetics?
- 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
What are the 9 places you would assess for dysmorphic features in a patient?
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
What would you specifically look for around the eyes when assessing for dysmorphic features?
- Palpebral fissures (size, slant)
| - Spacing (hypertelorism)
146
What is Hypertelorism?
Pupils too far apart
147
What would you specifically look for around the ears when assessing for dysmorphic features?
- Size, shape, position (low-set)
| - Rotation of the top ear anteriorly/posteriorly
148
When could someone have a thin upper lip?
Fetal alcohol syndrome
149
What would you specifically look for around the hands & feet when assessing for dysmorphic features?
- Palmar creases
| - Fingers & toes (correct number, polydactyly, syndactyly)
150
What can be 2 clinical signs of Velocardiofacial syndrome?
1. Prominent nose
| 2. Up-slanting palpebral fissures
151
What chromosome is deleted in Velocardiofacial syndrome?
22
152
What can be 3 clinical signs of Rubinstein Taybi syndrome?
1. Downslanting palpebral fissures
2. Microcephaly
3. Broad thumbs & big toes
153
What chromosome is deleted in Rubinstein Taybi syndrome?
16 (short arm)
154
What is pre-implantation genetic diagnosis (PGD)?
- 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
What are the 2 PROS of pre-implantation genetic diagnosis (PGD)?
1. Permits implantation of unaffected embryos
| 2. Termination of pregnancy is unnecessary
156
What are the 4 CONS of pre-implantation genetic diagnosis (PGD)?
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
What are the 3 stages in life that genetic screening tests are offered?
1. Pregnancy
2. Neonatal
3. Adulthood
158
What are the 6 main principles of a screening programme?
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
What is the sensitivity equation?
TP/(TP+TN)
- TP= true positive
- TN= true negative
160
What is the specificity equation?
TN/(TN+FP)
- TN= true negative
- FP= false positive
161
Describe how to do a neonatal screening test
Guthrie card blood spot from the heel of a baby
162
What are the 2 conditions which can be detected during neonatal screening by mass spectrometry?
1. Phenylketonuria
| 2. MCADD
163
What are 2 different diseases which can be screened postnatally?
1. Tay Sachs disease screening for Jewish people (pre-pregnancy)
2. Thalassaemia population carrier screening for thalassaemia
164
For pre-implantation diagnosis under what circumstances would you transfer the embryos to mother?
- Transfer only unaffected embryos
| - Up to 2 embryos
165
What pre-implantation genetic diagnostic test can tell embryo sexing for X-linked recessive conditions?
FISH
166
List 4 facts regarding genetic counselling?
1. Provides genetics-related advice & info
2. Advice should be non-directive
3. Info regarding investigation & interpretation
4. Thinking about implications for relatives
167
Describe CUBS in detecting Down Syndrome (combined ultrasound and biochemical screening)?
- Maternal blood biochemical markers
| - Ultrasound: nuchal translucency increases in down syndrome
168
What are the 2 conditions which can be detected during neonatal screening by immuno-assay?
1. Congenital hypothyroidism
| 2. Cystic fibrosis
169
What is the condition which can be detected during neonatal screening by High Performance Liquid Chromatography (HPLC)?
Sickle Cell disorder
170
Give 3 examples of neonatal screening tests?
1. Mass spectrometry
2. Immuno-assay
3. High Performance Liquid Chromatography (HPLC)
171
What are 3 situations when genetic diagnostic tests would be appropriate?
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
Give 2 examples of prenatal diagnostic tests?
1. Chorionic villous sampling
| 2. Amniocentesis
173
When can Chorionic villous sampling occur in pregnancy?
10-12 weeks
174
When can Amniocentesis occur in pregnancy?
16-18 weeks
175
What is the miscarriage rate for Chorionic villous sampling?
Up to 1/50
176
What is the miscarriage rate for Amniocentesis?
Up to 1/100
177
When do you get results back from Chorionic villous sampling?
<1 week
178
When do you get results back from Amniocentesis?
1-2 weeks
179
What are the 3 future developments for genetic diagnostic tests?
1. Array comparative genomic hybridization (aCGH)
2. Non-invasive prenatal diagnosis (NIPD)
3. Non-Invasive Prenatal Testing (NIPT) using next generation sequencing (NGS)
180
When would you use Array comparative genomic hybridization (aCGH)?
For foetuses with abnormal ultrasound scans
181
When would you use Non-invasive prenatal diagnosis (NIPD)?
- Achondroplasia
| - Fetal sex determination
182
When would you use Non-Invasive Prenatal Testing (NIPT)?
Aneuploidy (Down syndrome)
183
What is genomics?
- Concerns all the DNA
| - Nuclear (3 billion base pairs) & mitochondrial (17000 base pairs) genomes
184
What are 3 DNA-based detection methods?
1. Detection of point mutations
2. Detection of sub-microscopic duplications & deletions
3. Rapid detection of aneuploidies
185
What are the 2 ways that DNA sequencing can detect point mutations?
1. Automated fluorescent dideoxy (Sanger) sequencing 1 gene at a time
2. Massively parallel ("next-generation") sequencing many or all genes
186
What are the 2 ways of detecting sub-microscopic duplications & deletions?
1. MLPA (PCR-based)
| 2. Array comparative genomic hybridisation (aCGH)
187
What does Array comparative genomic hybridisation (aCGH) do?
- Looks across all the chromosomes at once
| - Looks for changes in the colour of millions of spots (yellow= normal, green/red= abnormal)
188
What is an Aneuploidy?
Abnormal number of chromosomes, that is not a multiple of 23 ie. trisomy 18
189
What is a way to rapidly detect aneuploidy?
Quantitative fluorescent PCR (QF-PCR)
190
Describe Quantitative fluorescent PCR (QF-PCR)?
- 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
What are the 2 chromosome-based analysis methods?
1. Karyotyping
| 2. FISH
192
What does FISH stand for?
Fluorescence in-situ hybridisation
193
Describe what FISH shows in Williams syndrome?
Deletion of elastin gene on 1 chromosome 7
194
Describe Karyotyping?
- Light microscopy
| - Resolution about 4-5Mb
195
What 4 things can you analyse with next generation sequencing?
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
What are the 2 types of DNA sequencing?
1. Sanger (fluorescent dideoxynucleotide) sequencing
| 2. Next generation (or massively parallel) sequencing
197
What is the most common method for next generation sequencing?
Illumina method
198
Describe the illumina method for next generation sequencing?
- Take image
- Fluorescence present where any base has been added
- Add one nucleotide/ Take image again
- Sequence is constructed by the computer
199
What is exome gene testing?
Analyses all the genes
200
What is non-invasive prenatal testing/diagnosis (NIPT/NIPD) testing?
Maternal plasma, free fetal DNA
201
What 3 things can non-invasive prenatal testing/diagnosis (NIPT/NIPD) be used for?
1. Fetal sex determination (X linked conditions)
2. Paternal mutations (FGFR3 mutation)
3. Testing for aneuploidy
202
What is the future development for next generation sequencing?
Sequencing of whole exomes/ whole genomes
203
In precision medicine what can the treatment be tailored to?
Specific disease-causing mutation (inherited mutation), in tumour cell (somatically acquired)
204
What disease is Ivacaftor used for?
Cystic fibrosis
205
Describe how Ivacaftor is used to treat cystic fibrosis?
It reopens the CFTR chloride ion channel which therefore goes onto help the lungs
206
What is the 3rd most common cystic fibrosis mutation?
G551D (present in 4% of patients)
207
What do the majority of non-small cell lung cancer patients present with?
Inoperable/metastatic disease
208
Give an example of a new targeted therapy for non-small cell lung cancer?
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
209
What is the gene mutation often found in breast cancer?
HER2 (human EGFR2)
210
What is the drug useful if there are too many copies of HER2 in breast cancer?
Trastuzumab (Herceptin)
211
What are the 2 possible future therapies for Duchenne muscular dystrophy?
1. Exon skipping
| 2. Drug to permit read-through of premature stop codons (Ataluren or PTC124)
212
Describe how exon skipping therapy can help with duchennes muscular dystrophy?
Convert duchennes muscular dystrophy to BMD phenotype by altering splicing patterns to correct the reading from with antisense oligonucleotides
213
Describe gene editing with CRISPR-CAS9 system?
- CRISPR is a guide RNA that finds the target sequence
| - Increased specificity recently with double nickase system
214
What is base editing?
Converting a G back to an A for example
215
What is a liquid biopsy?
Blood test looking for the tumours DNA mutation pattern
216
Would 2 different gene mutations located on the same copy of a gene lead to someone getting the disease?
NO
217
Could a female be affected by an X-linked disorder if she had a mutation on both of her X chromosomes?
YES
218
A boy has cystic fibrosis. What is the approx % chance of his mother's brother being a carrier?
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
A boy has cystic fibrosis. What is the approx chance that his healthy older sister is a carrier.
67%
220
What is a sub-microscopic gene?
One not able to be seen through a microscope (<4 million base pairs)
221
What is QF-PCR used most often in the diagnostic lab?
Trisomy of 21, 18 or 13 (rapid method)
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What can ARMS be commonly used for?
Single nucleotide substitution in a KNOWN position in a gene
223
What condition does NOT show genetic anticipation?
NF1
224
Describe why familial cancers with a mutated tumour suppressor genes are autosomal dominant and not recessive?
- 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
Could a man carry a BRCA1 or BRCA2 gene mutation?
YES as a carrier & has a 50% chance of passing it on
226
What 2 genes do proto-oncogenes include?
1. MYC gene
| 2. FOS gene
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What does DNA polymerase do?
Replication
