Genetics Flashcards
(141 cards)
1
Q
Multifactorial diseases recur in _ to _% of family members
A
2-7%
2
Q
What quantifies the relative contribution of genetic susceptibility to the predisposition to disease in a population?
A
Heritability
3
Q
List 4 human characteristics that show continuous normal distribution/polygenic inheritance?
A
Blood Pressure
Height
Intelligence
Head circumference
4
Q
What model accounts for dichotomous multifactorial disorders?
A
Threshold model
5
Q
______ is the sum of all of the factors which influence development of multifactorial disorder (genetic and environmental)
A
Liability
6
Q
At what point in a normal distribution will a person express a dichotomous multifactorial disease?
A
Threshold of liability
7
Q
“Relatives who share genes with X person will also have higher than average susceptibility depending on how many susceptibility genes they inherited”
What term describes this and what pattern of inheritance is X person likely to have?
A
Familial Clustering
Multifactorial Inheritance
8
Q
What do adoption studies do?
A
Separate effects of genes and family environments
9
Q
What is it called when two twins show a trait?
A
Concordance
This is higher in monozygotic twins than dizygotic twins, but still less than 100%
10
Q
What kind of study compares the frequency of a variant in affected patients versus that of a carefully matched control group?
A
Association Study
11
Q
What kind of inheritance does this describe:
“The disorder is familial but no distinctive pattern of inheritance”
A
Multifactorial
12
Q
What kind of inheritance does this describe:
“The recurrence risk is greatest among close relatives of the index case”
A
Multifactorial
13
Q
What kind of inheritance does this describe:
“Risk of recurrence is higher if more than one family member
is affected”
A
Multifactorial
14
Q
What kind of inheritance does this describe:
“Risk of disease is conditioned by severity”
A
Multifactorial
15
Q
What kind of inheritance does this describe:
“Recurrence risk changes between populations”
A
Multifactorial
16
Q
What kind of inheritance does this describe:
“recurrence risk is higher if the proband is of the lesser affected sex”
A
Multifactorial
17
Q
What is the respective risk for unilateral and bilateral cleft lip and palate?
A
2%, 6%
18
Q
What condition is caused by narrowing of the pylorus between stomach and intestine leading to obstruction and vomiting?
A
Pyloric Stenosis
19
Q
Pyloric stenosis is more common in one sex. Name the sex and how much more common it is?
A
5-times more common in baby boys.
20
Q
In Complement Factor H (CDH), a certain polymorphism confers a >5-fold increased risk to developing X disease.
Name the polymorphism and name X disease.
A
Y402H.
Age related Macular Degeneration.
21
Q
Name 4 examples of multifactorial disorders with congenital malformations.
A
Cleft lip and palate
Neural tube defects
Pyloric Stenosis
Congenital Heart Disease
22
Q
Name 4 examples of common adult diseases that are multifactorial disorders.
A
Diabetes Epilepsy Hypertension Schizophrenia Manic depression
23
Q
What do anterior neuropore defects give rise to?
A
Anencephaly
Encephalocele
24
Q
In neural tube defects, what do defects lower down in lumbar region cause?
A
Spina bifida
25
What is the recurrence risk of neural tube defects if you have one affected child?
4%
26
What is the recurrence risk of neural tube defects if you have two affected children?
10%
27
Name 3 groups that slight excess of neural tube defects are observed in.
1. Females
2. First Born
3. Babies conceived in late winter
28
What is the major environmental factor implicated in neural tube defects?
Maternal folic acid levels which acts via pathway of homocysteine metabolism
29
Supplementation of diet with folic acid (4mg/day) prior to conception has reduced recurrence risk from _% to _% in families that have NTD?
from 4% to 1%
30
What common polymorphism is found in methylenetetrahydrofolate reductase (MTHFR) gene (involved in neural tube defects)?
C677T
This allele is present in 30% of Irish population.
31
What percentage of Alzheimers Disease cases is inherited?
<5%
32
Name two cognitive Alzheimers disease symptoms
Memory Loss
| Disorientation
33
Name four behaviour Alzheimers disease symptoms
Anxiety
Delusions
Depression
Insomnia
34
The APO ε4 polymorphism is associated with:
Increased cholesterol and susceptibility to heart disease.
| Side note: This allele also increases risk for AD in a dose-dependent manner. This is the predisposing allele.
35
The APO ε2 polymorphism is associated with:
Decreased cholesterol
| Side note: This is the protective allele.
36
Young asymptomatic person with APO ε4/ε4 has __% lifetime risk of developing AD:
30%
37
Name 3 types of clinical sequencing
1. Multigene (panel) sequencing
2. Whole exome sequencing
3. Whole genome sequencing
38
Name 3 types of cytogenetic tests
1. Array Comparative Genomic Hybridisation (aCGH)
2. G-banding ('Karyotyping')
3. Fluorescence in situ Hybridisation (FISH)
39
What is constitutional cytogenetic analysis used for?
- Inherited and de novo chromosomal abberations
- Known chromosomal syndromes e.g. Down syndrome
- Prenatal diagnosis
40
What is oncology cytogenetic analysis used for?
- Acquired events
| - Chromosome aberrations present only in the cancer cell
41
When would a constitutional cytogenetic analysis be indicated?
- Newborns displaying dysmorphic features
- Infants and children displaying development delay e.g. mental disability
- Miscarriages
- For prenatal analysis where increase risk of chromosome abnormality
42
What does neoplasm refer to?
An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Neoplasms may be benign (not cancer) or malignant (cancer).
43
Use of cytogenetics in neoplastic disorders?
Diagnosis and prognosis of cancers
44
Name 4 sample types suitable for cytogenetic analysis
1. Blood
2. Chorionic villi
3. Bone marrow
4. Solid tumours
5. Solid tissue e.g. skin
45
What is the main test for postnatal indications requiring a chromosome analysis?
Array CGH
46
What are the clinical indications for microarray (aCGH)?
* Clinically significant abnormal growth -short stature, excessive growth, microcephaly, macrocephaly
* Abnormal clinical phenotype or dysmorphism
* Multiple congenital abnormalities
* Mental retardation or developmental delay
* Suspected deletion/ microdeletion/duplication syndrome
* X-linked recessive disorder in a female.
47
Microarray is ___ based
DNA based
48
Karyotype/FISH is ____ based
Cell based
49
What are the clinical indications for Karyotype/FISH analysis?
* Trisomy
* Numerical sex chromosome abnormality
* Ambiguous genitalia
* Family history of chromosome abnormality
* Mosaicism
50
What is the resolution of G-banding?
3-10Mb
51
What can aCGH not detect?
1. Balanced rearrangements
2. Low level mosaicism
3. Polyploidy (triploidy can be detected on a SNP array)
4. Uniparental disomy (can be detected on a SNP array)
52
What do meiotic nonallelic homologous recombination events between low-copy repeats (also known as segmental duplications) cause?
Microdeletion/duplication syndromes
53
Name the best known microdeletion syndrome.
DiGeorge syndrome (22q11.2)
54
What is the gold standard diagnostic test for DiGeorge syndrome?
Microarray
55
Why microarray rather than FISH for the detection of microdeletions?
In the event of no deletion the rest of the genome can be investigated
56
Name 3 types of FISH probes
1. Paint
2. Centromeric
3. Locus specific (LSI)
57
What is the minimum resolution for G-band?
5Mb
58
What is the minimum resolution for microarray?
50kb
59
What is the minimum resolution for FISH?
200kb
60
Name an advantage of G-band tests
Can detect balanced rearrangements
61
Name an advantage of Array tests
Whole genome screen, higher resolution than G-band
62
Name an advantage of FISH tests
Can detect balanced rearrangements; higher resolution than G-band
63
Name a limitation of G-band tests
Time consuming, low resolution
64
Name a limitation of Array tests
Cannot detect balanced rearrangements or low level mosaicism
65
Name a limitation of FISH
Targeted analysis (i.e., need to know what you are looking for)
66
Name 4 molecular genetic samples
1. Blood
2. Amniocytes
3. Chorionic villi
4. Circulating tumour DNA
67
What molecular genetic test is used to diagnose breast cancer?
Sequence the entire coding region
68
What molecular genetic test is used to diagnose Huntington Disease (which is always caused by CAG repeat expansion)?
Size the repeat region by PCR
69
What is target detection used for in molecular genetic diagnosis?
Test for specific characterised mutation in a specific exon of the gene of interest...
- Family mutation (e.g. BrCa)
- Commonly known mutations (e.g. CF)
- Inexpensive, rapid analysis
70
What is scanning detection used for in molecular genetic diagnosis?
Analysis of the whole gene for a disorder to determine whether there is a mutation present that could be causing the disease.
- BrCa, CF (if common mutations are absent)
- More expensive and more time-consuming
71
Name 4 uses of PCR
1. Detection (e.g. detecting deletions)
2. Quantitation (Real-time PCR)
3. Sizing (e.g. Triplet repeat expansions)
4. Genotyping (e.g. known mutations)
72
What does constitutional microarray analysis do?
Reveals gains and losses genome-wide
73
Name 5 applications of next-generation DNA sequencing
1. Targeted resequencing
2. Gene panels for specific disorders
3. Whole exome sequencing
4. Whole genome sequencing
5. Trisomy sequencing
74
What term describes this: 'The probability that the test will be negative if the patient does not have the disease'
Clinical specificity
75
How many protein-coding genes are in the human genome?
20,000-25,000 protein-coding genes
76
What is the term for 1) methylated cytosine and 2) its oxidised form?
1) 5-methyl cytosine
| 2) 5-hydroxy methyl cytosine
77
Name 4 mechanisms of epigenetic regulation
1. DNA methylation
2. RNA methylation
3. Post-translational modifications of histones
4. Antisense regulation
78
What proteins cause DNA to be methylated?
DNA methyl transferases (DNMT1, DNMT2, DNMT3)
79
What proteins cause DNA to be demethylated?
TETs (Ten-Eleven-Translocation)
80
What conversion do TETs mediate in DNA demethylation?
5-methyl-C to 5-hydroxymethyl-C
81
Are histone subunits positively charged or negatively charged?
The histone subunits are positively charged, thus allowing the compaction of the negatively charged DNA
82
Name 4 kinds of histone modifications
1. Acetylation
2. Methylation (lysines)
3. Phosphorylation
4. Ubiquitylation
83
Name 4 histones
H2A, H2B, H3, H4
84
In loosely packed euchromatin, transcription is ________
In loosely packed euchromatin, transcription is active
85
In tightly packed heterochromatin, transcription is ________
In tightly packed heterochromatin, transcription is inactive
86
Name 2 functions of long noncoding RNA
1. can facilitate transcription factor binding and thus promote gene activation
2. may act as scaffolding to stabilise secondary or tertiary structures
87
Name 4 systems epigenetics is involved in:
1. Development
2. Stem cells
3. Chromosome X inactivation
4. Genomic imprinting
88
Name 3 imprinting disorders
1. Prader-Willi Syndrome
2. Angelman Syndrome
3. Beckwith-Wieldemann Syndrome
89
What does this describe: "The epigenetic marking of a locus on the basis of parental origin, which results in monoallelic gene expression."
Genomic imprinting
90
How many genes in the human genome are imprinted?
>200 genes
91
When/where are imprints set?
In the parental germ cells
92
What is the allele specific gene expression in imprinted genes based on?
Parent-of-origin
93
Name 2 paternally expressed imprinted genes (growth promoters)
IGF2
| PEG1
94
Name 2 maternally expressed imprinted genes (growth suppressors)
H19
| L23
95
What is the chromosomal region affected in Prader-WIlli Syndrome (PWS) and Angelman Syndrome (AS)?
15q11-q13
96
What is the chromosomal region affected in Beckwith Weidemann Syndrome [BWS]/Sporadic Cancer?
11p15.5
97
What is the incidence of Prader-Willi Syndrome?
1 in 15,000 people
98
What is the key feature of Prader-Willi Syndrome?
Constant sense of hunger that usually begins at 2 years of age (Hyperphagia)
99
What is the most common genetic cause of obesity?
Prader-Willi Syndrome
100
Name the disorder associated with the following facial features:
Narrow face, almond shaped eyes, small appearing mouth, a thin upper lip with downturned corners of the mouth, crossed-eyes
Prader-Willi Syndrome
101
Name the disorder associated with the following clinical presentations:
Profound intellectual deficiency, absent speech, microcephaly, ataxic gait, paroxysmal laughter
Angelman Syndrome
102
How is Angelman Syndrome managed?
- Speech therapy
- Anticonvulsant medication
- Occupational therapy
103
How is Prader-WIlli Syndrome caused?
Paternal loss of 15q (imprinting disorder)
104
How is Angelman Syndrome caused?
Maternal loss of 15q (imprinting disorder)
105
What is the candidate gene involved in Prader-Willi Syndrome?
SNRPN
106
What is the candidate gene involved in Angelman Syndrome?
UBE3A
107
Name the disorder associated with the following clinical presentations:
Pre and postnatal overgrowth of up to 160% of normal birthweight, Macroglossia (protruding tongue), Visceromegaly (enlarged organs), Exomphalos (part of the bowel on the outside)
Beckwith-Wiedemann Syndrome
108
What is the estimated risk for tumour development in children with Beckwith-Wiedemann syndrome in the first 8 years of life?
7.5%
109
_________ refers to the entire spectrum of genes that determine drug behavior and sensitivity
Pharmacogenomics refers to the entire spectrum of genes that determine drug behavior and sensitivity
110
___________ is often used to define the more narrow spectrum of inherited differences in drug metabolism and disposition
Pharmacogenetics is often used to define the more narrow spectrum of inherited differences in drug metabolism and disposition
111
Name a drug that exhibits inherited variations in drug metabolism, specifically because of acetylation.
Hydralazine.
Hydralazine is an antihypertensive that is inactivated by acetylation. Slow acetylator phenotype can get hydralazine-induced lupus.
Other drugs include sulfonamides and dapsone caffeine.
112
What percentage of Caucasians carry the variant allele TMPT*3A?
5%
113
Name 3 drugs that thiopurine S-methyltransferase (TPMT) catalyses the methylation of
1. 6-mercaptopurine
2. Azathiopurine
3. Thioguanine
114
Name a genetic polymorphism that is included in drug labelling
Thiopurine S-methyltransferase (TPMT) genetic polymorphisms
115
What are people with the TMPT*3A polymorphism at risk of?
Life-threatening myelosuppression
116
Name 4 types of drugs that CYP2D6 metabolises
1. Anti-depressants (Fluoxetine)
2. Neuroleptics (Haloperidol)
3. Opioids (Codeine)
4. Antihypertensives (Debrisoquine)
117
What are the molecular genetic mechanisms responsible for variation in CYP2D6 activity?
- Non-synonymous SNPs
- Gene deletion
- Gene duplication
118
Cytochrome P450 2D6 (CYP2D6) pharmacogenetics determined using the ratio of debrisoquine to its metabolite, ___________
Cytochrome P450 2D6 (CYP2D6) pharmacogenetics determined using the ratio of debrisoquine to its metabolite, 4-hydroxydebrisoquine
119
What are CYP2D6 ultrametabolisers at risk of when given standard codeine doses?
Respiratory depression
120
Who has the worst outcomes when treated with tamoxifen?
a) Poor metabolisers
b) Intermediate metabolisers
c) Extensive metabolisers
Poor metabolisers
121
What enzymes does the anti-platelet drug, clopidogrel, rely on for activation?
CYP3A4 and CYP2C19
122
What is the common dose of clopidogrel?
75mg/day
123
Mutations in what gene causes rare cases of warfarin resistance:
VKORC1
124
What is a haplotype?
Combination of SNPs on a single chromosome
125
VKORC1 haplotype is associated with approximately __% to __% of the variance in the warfarin maintenance dose
VKORC1 haplotype is associated with approximately 25% to 30% of the variance in the warfarin maintenance dose
126
Which isomer of warfarin is more potent?
S-warfarin is 3-5x more potent than R-warfarin
127
What is S-warfarin metabolised by?
CYP2C9
128
What are poor metabolisers of warfarin at increased risk of?
Haemorrhage
129
Name two disadvantages of genetic counselling for a patient.
- Psychological burden (guilt/anxiety)
| - Implications for relatives
130
A 25 year old girl is seeking predictive testing for a BrCa1 mutation that was found in her mother. What is the risk that she would have inherited the same mutation?
50% risk
131
What are the risks of inheriting a BrCa1 mutation?
High lifetime risk of breast and ovarian cancer
132
List two reasons why someone may see a genetic counsellor while pregnant? (Prenatal referral)
1. History of miscarriage/foetal abnormalities
| 2. Abnormality picked up on ultrasound scan
133
Name a disease that commonly results in a genetic counselling referral after new born screening.
Cystic Fibrosis
134
What is the success rate of preimplantation genetic diagnosis (PDG)?
30% success rate
135
Name two types of invasive testing during pregnancy
1. Chorionic villus sampling (CVS), from between 11-13 weeks
| 2. Amniocentesis, from 15 weeks
136
Name 2 advantages of gene panels (next generation-sequencing panels)
1. Relatively cheap
| 2. Fewer unexpected findings
137
Name 2 advantages of whole exome sequencing
1. Don't need hypothesis
| 2. Trios more accurate
138
Name 2 disadvantages of whole genome sequencing
1. Risk of unexpected findings
| 2. Time consuming and difficult to analyse
139
Name 2 types of protein-truncating variants (mutations)
1. Nonsense
| 2. Frameshift
140
Name a targeted therapy for cystic fibrosis
Ivacaftor / Lumacaftor
141
Name an emerging genome editing technique
CRISPR/Cas9
