L16 - Bristol Genetics Flashcards
1
Q
What is the primary purpose of clinical genomic testing?
A
To aid diagnosis, prognosis, treatment selection, and disease monitoring
2
Q
What types of diseases benefit from genomic testing?
A
Rare diseases, cancers, infectious diseases
3
Q
What are germline mutations?
A
Genetic changes inherited from parents and present in every cell
4
Q
What are somatic mutations?
A
Acquired genetic changes in cells after conception
5
Q
How can genomic testing influence treatment decisions?
A
It helps tailor personalised treatments and predict responses or resistance
6
Q
What is the function of next generation sequencing in diagnostics?
A
It allows analysis of many genes simultaneously for mutations
7
Q
What is the difference between gene panels and whole genome sequencing?
A
Gene panels target selected genes; whole genome sequencing covers everything
8
Q
What are the advantages of gene panels?
A
Targeted, cheaper, quicker, good when candidate genes are known
9
Q
What are the advantages of whole genome sequencing?
A
Covers all coding and non-coding areas, can identify unknown variants
10
Q
What diseases are often diagnosed using gene panels?
A
Cancer and haematological conditions
11
Q
How does the NHS organise genomic testing services?
A
Through seven regional Genomic Laboratory Hubs
12
Q
How many NHS Genomic Laboratory Hubs are there in England?
A
Seven
13
Q
What kind of variants are usually seen in rare diseases?
A
Germline variants
14
Q
What kind of variants are usually seen in cancers?
A
Somatic variants
15
Q
What is the genetic defect in Haemophilia A?
A
Factor VIII deficiency (F8 gene, Xq28)
16
Q
What is the genetic defect in Haemophilia B?
A
Factor IX deficiency (F9 gene, Xq27.1)
17
Q
How is haemophilia inherited?
A
X-linked recessive inheritance
18
Q
Why are males more affected by haemophilia than females?
A
Males have only one X chromosome, so a mutation will show the phenotype
19
Q
What are the symptoms of haemophilia?
A
Easy bruising, joint bleeding, pain, prolonged bleeding
20
Q
What type of mutation causes severe haemophilia?
A
Deletions, insertions, nonsense or splice-site mutations
21
Q
What type of mutation causes mild haemophilia?
A
Missense mutations
22
Q
What is haemophilic arthropathy?
A
Joint damage from repeated bleeding episodes
23
Q
How were clotting factors historically sourced?
A
From pooled blood plasma of donors
24
Q
What viruses were transmitted through contaminated blood products?
A
HIV and HCV
25
What is Kaposi's sarcoma?
A vascular tumour linked to immune suppression and HIV
26
What is the inheritance pattern of haemophilia?
Sex-linked recessive inheritance
27
What is the chance a male baby has haemophilia if his mother is a carrier?
50% if mother is a carrier and fetus is male
28
How can the risk of a fetus having haemophilia be determined?
Via genetic testing of the mother and fetus
29
What gene is typically mutated in severe haemophilia A?
INV22 in the F8 gene
30
What prenatal options are available to test for haemophilia?
Chorionic villus sampling, amniocentesis, or maternal blood testing
31
How can preimplantation genetic diagnosis be used in haemophilia?
By selecting embryos without the mutation during IVF
32
How does haemophilia affect joint health over time?
Repeated bleeding causes joint damage and inflammation
33
What is the BCR-ABL fusion gene?
A fusion of BCR and ABL genes with increased tyrosine kinase activity
34
What type of cancer is associated with the BCR-ABL fusion gene?
Chronic myeloid leukaemia (CML)
35
What chromosomal translocation causes the Philadelphia chromosome?
t(9;22)(q34;q11)
36
What is Imatinib used to treat?
CML
37
How does Imatinib work?
It inhibits BCR-ABL tyrosine kinase
38
What is the mechanism of resistance to Imatinib?
By acquiring new mutations in the ABL gene
39
What is the treatment if Imatinib resistance develops?
Use of second- or third-generation TK inhibitors
40
How can genetic testing monitor chronic myeloid leukaemia (CML)?
By measuring BCR-ABL transcript levels over time
41
How does CML typically present clinically?
Fatigue, weight loss, fever, splenomegaly
42
What is the effect of CML on blood cell counts?
High white cell count, low red cells, sometimes high platelets
43
What age group is most commonly affected by CML?
40–60 years old
44
What is a Circos plot used for?
Visualises chromosomal changes and copy number variation
45
What is minimal residual disease (MRD)?
Residual disease below clinical detection after treatment
46
What genetic variant is associated with adverse fluorouracil reactions?
DPYD variant
47
What is pharmacogenomics?
The study of how genes affect drug response
48
What is a familial mutation example mentioned in the lecture?
GATA1 deficiency
49
How is Down syndrome genetically characterised?
Trisomy 21
50
What is the pattern of inheritance for polycystic kidney disease?
Autosomal dominant inheritance
51
What is the genetic cause of sickle cell disease?
Mutation in the β-globin gene
52
What are germline mutations present in?
All cells derived from the fertilised egg
53
What is the benefit of testing fetal DNA from maternal blood?
It is non-invasive and safe for the fetus
54
What types of mutations can whole genome sequencing detect?
Single nucleotide changes, insertions, deletions, and CNVs
55
What is the advantage of rapid genome sequencing turnaround?
Quick turnaround (<4 weeks) and low cost
56
What is Noonan syndrome?
A developmental disorder with multiple features
57
How can Marfan syndrome be identified clinically?
Tall, slender body, long limbs, joint flexibility
58
What is the major cardiovascular risk in Marfan syndrome?
Aortic aneurysm or dissection
59
Why is genetic testing helpful in BRCA mutation cases?
To assess cancer risk, family risk, and treatment implications
60
How does DPYD variant affect chemotherapy treatment?
Increased risk of severe side effects from fluorouracil
61
What are soft tissue tumours often characterised by?
Chromosomal translocations
62
How are soft tissue tumours tested genetically?
By sequencing for known translocations or mutations
63
Why might additional findings in tumour genetic testing matter?
They might suggest alternative treatments or clinical trial inclusion
64
What is an actionable mutation?
A mutation linked to a specific treatment or drug response
65
What is the role of genomics in infectious disease diagnosis?
Identifying pathogen DNA or RNA for diagnosis and resistance
66
Why is genetic testing preferred over culturing Mycobacterium tuberculosis?
M. tuberculosis grows slowly and is hard to culture
67
How long does it take to culture tuberculosis traditionally?
Around four weeks
68
What is the benefit of genomic testing in suspected tuberculosis cases?
Faster, more reliable, and accurate than culture
69
What does whole genome sequencing cover that gene panels may not?
Regulatory, intronic, and non-coding regions
70
What tissues can be used for whole genome sequencing in somatic disease?
From skin, blood, or tumour samples
71
What is the role of bioinformatics in next generation sequencing?
For aligning, analysing and interpreting sequencing data
72
What are regulatory DNA regions included in sequencing?
Promoters, enhancers, silencers, insulators
73
What kind of inheritance does haemophilia follow?
X-linked recessive
74
What coagulation factor is deficient in haemophilia A?
Factor VIII
75
What coagulation factor is deficient in haemophilia B?
Factor IX
76
What is the prevalence of haemophilia A?
1 in 5,000 males
77
What is the prevalence of haemophilia B?
1 in 30,000 males
78
What is the NHS Genomic Test Directory?
A guide listing test indications and technologies for genomics
79
How many rare disease test indications are listed in the directory?
3,000 rare disease tests
80
How many cancer test indications are listed in the directory?
180 cancer tests
81
What is chronic synovitis?
Chronic joint inflammation
82
What type of inheritance leads to increased tumour risk in syndromic diseases?
Germline mutation inheritance
83
How does genomic testing improve prognosis estimation?
By identifying likely disease severity and therapy responses
84
How can genomics help with patient stratification in clinical trials?
By identifying patients eligible based on tumour genetics
85
What is the potential of tumour and germline genome sequencing together?
To distinguish between inherited and acquired mutations, improving insight
86
What type of diseases can genomic testing help diagnose beyond rare diseases?
Genomic testing can help diagnose common malignancies, metabolic diseases, and infectious diseases.
87
What is the key difference between germline and somatic mutations?
Germline mutations are inherited and present in every cell; somatic mutations occur later in specific cells.
88
How does genomic testing help in early metabolic disease detection?
Early detection allows targeted management like dietary modifications for metabolic disorders.
89
What is polycystic kidney disease and how is it inherited?
Polycystic kidney disease is a dominantly inherited disorder causing cyst formation in kidneys.
90
Why does polycystic kidney disease severely damage the kidney?
It replaces functional kidney tissue with cysts, leading to organ enlargement and failure.
91
What condition is characterised by defective collagen fibres and a tall, slender build?
Marfan syndrome is a connective tissue disorder with long limbs and joint hypermobility.
92
What is a major cardiovascular complication seen in Marfan syndrome?
Aortic aneurysms and dissections are major cardiovascular risks in Marfan syndrome.
93
How does assessing fetal DNA from maternal blood improve prenatal testing?
It allows non-invasive prenatal screening, avoiding risks of amniocentesis or chorionic villus sampling.
94
What is the genetic defect underlying familial adenomatous polyposis (FAP)?
FAP results from germline mutations in the APC gene leading to early-onset colorectal adenomas.
95
How does familial adenomatous polyposis differ from sporadic colorectal cancer?
Unlike sporadic colorectal cancer, FAP arises much earlier and involves multiple polyps.
96
Why is next-generation sequencing useful even when a single-gene test would suffice?
Next-generation sequencing can uncover unexpected actionable mutations and refine diagnosis.
97
How has genetic testing improved tuberculosis (TB) diagnosis?
Genetic testing enables rapid TB diagnosis without waiting for slow bacterial culture growth.
98
What is an actionable mutation in tumour genetic profiling?
An actionable mutation indicates a genetic change that suggests a targeted treatment option.
99
Why do soft tissue tumours often require genetic testing for accurate diagnosis?
Soft tissue tumours often have characteristic translocations that aid diagnosis via genetic testing.
100
How does somatic versus germline testing improve understanding of cancer development?
Somatic testing identifies tumour-specific changes; germline testing reveals inherited predisposition.
101
What is the role of Southmead Hospital in NHS genomic testing?
Southmead Hospital is a major hub for genomic testing in the South and Southwest of England.
102
Why was Queen Victoria important in the history of haemophilia?
Queen Victoria was a known carrier of haemophilia B, significantly affecting royal family descendants.
103
What are typical symptoms of haemophilia?
Typical symptoms include easy bruising, joint bleeding, swelling, and pain.
104
How do missense mutations affect the severity of haemophilia?
Missense mutations tend to cause milder or moderate forms of haemophilia compared to deletions.
105
What is haemophilic arthropathy?
Haemophilic arthropathy is joint damage caused by repeated bleeding episodes.
106
What led to the blood product scandals in haemophilia treatment?
Contaminated blood products from desperate donors led to transmission of HIV and HCV.
107
What is Kaposi sarcoma and how is it linked to HIV?
Kaposi sarcoma is a vascular tumour often seen in immunocompromised HIV patients.
108
How does Hepatitis C virus relate to past haemophilia treatments?
Hepatitis C virus was transmitted through infected blood products before screening improved.
109
What is the genetic cause of chronic myeloid leukaemia (CML)?
CML is caused by a translocation between chromosomes 9 and 22, creating the Philadelphia chromosome.
110
What is the Philadelphia chromosome?
The Philadelphia chromosome is a shortened chromosome 22 formed by translocation.
111
What fusion gene is created in CML and what is its effect?
The BCR-ABL fusion gene drives uncontrolled proliferation by activating tyrosine kinase signaling.
112
How does Imatinib revolutionize CML treatment?
Imatinib specifically inhibits BCR-ABL tyrosine kinase, dramatically improving CML outcomes.
113
Why do patients eventually develop resistance to Imatinib?
Resistance develops through secondary mutations in BCR-ABL or selection of resistant clones.
114
How can monitoring BCR-ABL transcript levels guide CML management?
Measuring BCR-ABL transcript levels helps assess response and detect emerging resistance.
115
What is the principle behind using tyrosine kinase inhibitors in cancer therapy?
Targeting tyrosine kinases blocks proliferative signals specific to cancer cells.
116
