Genetics Flashcards
(104 cards)
1
Q
What is a congenital abnormality?
A
Condition exiting at birth
2
Q
What is a malformation?
A
Primary structural defect e.g atrial septal defect
3
Q
What is a disruption?
A
Secondary abnormal structure. Not genetic, but genetic factors predispose.
4
Q
What is a deformation?
A
Abnormal mechanical force distorting a structure. E.g hip dislocation. Occurs late n pregnancy.
5
Q
What is a syndrome?
A
A pattern of abnormalities with a specific underlying cause
6
Q
What is a dysplasia?
A
Abnormal organisation of cells into tissue.
7
Q
What is a sequence?
A
Multiple abnormalities initiated by a primary factor.
8
Q
What is an association?
A
Non-random occurrence of abnormalities with typically unknown cause.
9
Q
What is a centromere? How does the position of the centromere dictate the type of chromosome?
A
Centromere is the point of attachment of the sister chromatids.
If the centromere is in the middle, it is metacentric.
If the centromere is just off the middle, it is submetacentric.
If the centromere is not in the middle, it is acrocentric. The small ends are called satellites (p), the long arms are q.
10
Q
What are the different types of chromosomal abnormalities?
A
- Aneuploidy (numerical)
- Structural (translocations, deletions, insertions, inversions, rings)
- Mosaicism (different cell lineages)
11
Q
What are the different types of aneuploidy, and how lethal are they? What is the name given to this difference?
A
Monosomy = always lethal Trisomy = can be tolerated Tetrasomy = can be tolerated
This is due to dosage compensation
12
Q
What is partial aneuploidy? What are the two different types?
A
Partial aneuploidy is where part of a chromosome is translocated to another chromosome.
Balanced aneuploidy is where no genetic information is lost or gained.
Unbalanced aneuploidy is where there is gain or loss of genetic information (this happens in the gametes of balanced aneuploidy individuals.
13
Q
Give an example of a trisomy condition with the clinical features
A
Trisomy 21 = Downs Syndorme
Clinical features include:
- Severe hypotonia, sleepyness and excess nuchal skin in newborns
- Macroglossia, small ears
- Single palmar crease, wide gap between first and second toes
- Atrial and ventricular septal defects
- Low IQ (25-75)
- Happy and affectionate
- Advanced social skills
- Increased risk of Leukaemia and Alzheimer’s
14
Q
What are the causes of Trisomy 21 (and their relative percentages)?
A
- Non-disjunction of homologous chromosomes in meiosis 1 (95%)
- Robertsonian translocation (4%)
- Mosaicism (1%)
15
Q
Give an example of a monosomy condition with the clinical features
A
Monosomy X = Turner's syndrome Clinical features: - Generalised oedema and swelling in the neck seen in 2nd trimester - puffy extremities at birth - low posterior hairline - Normal intelligence - Short stature - Ovarial failure
16
Q
Give an example of a sex chromosome aneuploidy condition with the clinical features (excluding Turner’s)
A
XXY = Kleinfelter’s Syndrome
Clinical features:
- Clumsiness, verbal learning difficulties
- Taller than average
- Infertile
- Increased risk of leg ulcers, osteoporosis and breast carcinomas in adults
17
Q
Give two examples of trisomy conditions
A
Trisomy 12 - Patau syndrome. Presents heart defects and mental retardation. Median survival age is 2.5 days
Trisomy 18 - Edwards Syndrome. Presents with heart defects, kidney malformation and digestive tract defects and mental retardation.
18
Q
How is it possible to be XX or XY and phenotypically opposite?
A
Translocation of the Sex Determining Region (SRY) on the Y chromosome. The SRY is activated 6 weeks post-conception and signals the development of the testes.
19
Q
What is a genomic disorder?
A
A disorder caused by loss or gain of DNA (micro -deletion or micro-duplication).
20
Q
Give an example of a micro-deletion genomic disorder
A
Di George Syndrome caused my micro-deletion of the 22q11.2 region containing the gene TBX1. Patient presents with congenital heart disease, palatal abnormalities, thymic/parathymic hypoplasia and characteristic faces.
21
Q
Give an example of a micro-duplication genomic disorder
A
Charcot-Marie-Tooth disease 1A is caused by micro-duplication of the PMP22 gene on chromosome 17
Patient presents with muscle weakness, hypotonia and misses reflexes.
22
Q
What is a pedigree?
A
A diagram used to show inheritance
23
Q
Contrast the features of monogenic and complex disorders.
A
Monogenic: - clear inheritance - no environmental factors - rare Complex: - unclear inheritance - environmental factors - common
24
Q
What is a mutation?
A
A heritable change in DNA sequence
25
What is a polymorphism?
A frequent mutation
26
What are the types of point-mutations?
Missense - codes for another amino acid
| Nonsense - codes for stop :(
27
What are the types of mendelian inheritance patterns?
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-lined recessive
- Mitochondrial
- Co-dominant
28
Name an autosomal dominant disease
Huntington's diesease.
29
What are the clinical features of Huntington's disease?
- Motor, cognitive and psychiatric dysfunction
- Mean age of onset is 35-44 years
- Mean survival time is 15-18 years
30
What is the pathophysiology of Huntington's disease?
The HTT gene on Chromosome 4 encodes a protein called huntingtin. Huntington's patients have an altered gene which encodes a toxic form of the protein that forms clumps and cell death in the basal ganglia of the brain.
The altered gene is caused by an unstable triplet repeat of CAG. The number of repeats may expand with each generation.
40 repeats = affected patients
31
What are the clinical features of Cystic Fibrosis?
Thick mucus in lungs causes breathing problems and repeated infections. Blockages in pancreas affects digestive enzymes.
Treatment consists of daily enzymes and physiotherapy.
In the UK, 1 in 22 are carriers
32
What is the pathophysiology of Cystic Fibrosis?
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The CFTR (Cystic fibrosis transmembrane conductance regulator) gene on Chromosome 7 encodes a protein called the CFTR.
Absence of a functioning CFTR gene affects chloride ion channel formation in epithelial cells. This disrupts salt/water regulation and lead stop thick mucus.
The mutation affects the folding of CFTR protein, preventing it to moving to it's correct place in the cell membrane.
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33
What two diseases can be caused by a mutation in the CFTR gene?
- cystic fibrosis
| - congenital absence of the vas deferens (CAVD)
34
Name an example of an X-linked recessive disease
Haemophilia
35
What are the clinical features of Haemophilia?
- Bruise easily
- Bleed for longer
Two types, A and B
Treated with injections of clotting factor
36
What is the pathophysiology of haemophilia?
Haemophilia A: The F8 gene on Chromosome X encodes a protein called coagulation factor VIII. A lacking functioning allele causes symptoms.
Haemophilia B: A mutation in the F9 gene on Chromosome X affects coagulation factor IX.
Symptoms identical to Haemophilia A.
37
What is incomplete penetrance?
Symptoms not always present in an individual because of other genes in genome
38
What is variable expressivity?
Disease severity may vary between individuals
39
What is phenocopy?
Having the same disease but with a different underlying cause
40
What is epistasis?
Interaction between disease gene mutations and other modifier genes can affect genotype.
41
What is the difference in the strategies to combat recessive and dominant disorders?
Treatment for dominant disorders aim to neutralise the toxic protein/effects of gene
Treatment for recessive disorder aim to restore activity of missing protein.
42
What are imprinted genes?
Where you inherit only one copy because the other is epigenetically silenced.
43
How are genes usually epigenetically silenced?
DNA methylation to the 5 position of the pyramiding ring of cytosine.
44
Name two examples of diseases caused by imprinting, and what chromosome they affect.
Prader-Willi results from the loss of paternal chromosome 15.
Angelman Syndroms results from the loss of maternal chromosome 15.
45
What are the clinical features of Prader-Willi syndrome?
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Symptoms include:
- Hyperphagia
- Obesity and diabetes
- Mental retardation
- Muscle hypotonia
- Short stature
- Delayed or incomplete puberty
- Infertility
Managed by diet restriction and exercise. Growth hormone treatment and hormone replacement therapy.
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46
What are the pathophysiological mechanisms of Prader-Willi syndrome?
Lack of functional PWS critical region on 15q11-q13.
70% due to deletion of critical region
25% due to inheritance of two maternal copies by uniparental isodisomy
5% due to other mechanisms such as translocations
47
What is uniparental isodisomy?
Non-disjunction in meiosis II.
Zygote has 3 chromosomes (trisomy) but one is deleted. However in the case of Prader-Willi, the parental chromosome is needed.
48
What are the clinical features of Angelman syndrome?
Severe developmental delay. Poor or absent speech. Gait ataxia. Seizures.
Treated with anti-convulsants, physiotherapy and communication therapy.
49
What are the properties of the mitochondrial genome?
16.6 Kb
37 genes
2-10 copies per mitochondrion
50
Why can mitochondrial diseases have variable?
Heteroplasty of a mixture of mitochondria - some containing mutant DNA, others containing normal DNA.
51
Name two mitochondrial diseases
MELAS and LHON
52
Describe the clinical features of MELAS
MELAS stands for
Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke.
It is a progressive neurodegenerative disorder diagnosed by muscle biopsy.
53
What is the pathophysiology of MELAS?
Single mutation in several genes:
- MTTL1 is a tRNA that is changed so that it translates phe instead of leu.
- MTND1 and MTND2 change NADH dehydrogenase subunits 1 and 5
54
Describe the clinical features of LHON
LHON stands for
| Leber's Hereditary Optic Neuropathy. It causes bilateral painless loss of central vision and optic neuropathy.
55
Name two inborn errors of metabolism?
Phenylketonuria and MCAD deficiency.
56
What are the clinical features of phenylketonuria?
Severe mental retardation; convulsions; blue eyes and blond hair. Treated by early screening and removing of phenylalanine from diet.
57
What is the pathophysiology of phenylketonuria?
Deficiency of enzyme phenylalanine hydroxylase, causing phenylalanine to accumulate. Also causes tyrosine deficiency, leading to reduced melanin.
58
What are the clinical features of MCAD deficiency?
Medium-chain Acyl-CoA Dehydrogenase (MCAD) deficiency presents as coma, metabolic acidosis and encephalopathy. Tackled by maintaining adequate calorie intake to prevent switching to fatty acid oxidation.
59
What is the pathophysiology of MCAD deficiency?
Lack of medium-chain acyl-CoA dehydrogenase enzyme means people cannot break down fats.
60
How is cancer caused by genetic changes?
An accumulations of genetic changes lead to altered levels of transcriptions or aberrant gene transcripts. This activates signal transduction pathways that confer selective advantages to the cell.
Commonly affected pathways include those that control the cell cycle, proliferation, apoptosis and adhesion.
61
Differentiate between the two classes of cancer genes
Oncogenes are those that promote cell cycle. Increased expression lead to cancer.
Tumour suppressors control cell division. Mutation of these may lead to uncontrolled cell division.
62
What are haplosufficient tumour suppressor genes?
Most TS genes require inactivation of both copies to cause a malignancy. A few TS genes only require damage to one, making them haplosufficient.
63
What is loss of heterozygosity?
TS genes in which a hit involves deletion of a large surrounding area of the chromosome.
Searching for LOH regions was a primitive was of finding cancer cells.
64
What mutations confer an inherited predisposition to breast and ovarian cancer?
Mutated BRCA1 and BRCA 2 genes confer a 60% risk of developing breast cancer, and an increased risk of ovarian cancer.
Normal BRCA1 and BRCA2 genes are involved in DNA repair.
65
What mutations confer an inherited predisposition to colorectal cancer?
Mutated APC (Adenomatous Polyposis Coli) gene causes FAP (Familial Adenomatous Polyposis) which is responsible for 1% of colorectal cancers. It gives a virtually 100% risk of cancer in a lifetime.
Mutated MLH1 or MLH2 (DNA repair genes) cause Hereditary Non-Polyposis Colorectal Cancer (Lynch syndrome) which increases risk of colorectal cancer to 80%, causing 3% of all colorectal cancers.
66
Why were cytogenetic investigations extensive in haematological malignancies?
- Leukaemic genomes are more stable
| - Easier to perform actual tests on circulating cells
67
What is the pathophysiology of Chronic Myeloid Leukaemia?
Chronic Myeloid Leukaemia is a clonal myeloproliferative disorder of the pluripotent haematopoietic stem cells leading to an overproduction of mature granulocytes.
68
What are the consistent pathogenomic markers for Chronic Myeloid Leukaemia?
A translocation t(9;22) resulting in a fusion gene called BCR-ABL1
69
What is the pathophysiology of Acute Promylogenic Leukaemia?
Abndomal accumulation of immature granulocytes (promyelocytes).
The fusion gene product of t(15,17)(q22;q12) called the PML-RAR(alpha) protein binds strongly to DNA blocking transcription via enhanced interaction with co-repressor molecules.
70
How is acute promyelogenic leukaemia treated?
All Trans Retinoid Acid (ATRA) therapy. This dissociates co-repressors allowing normal transcription.
71
What is pharmacogenomics?
A branch of pharmacology which deals with the influence of genetic variation on a drug response.
72
Name the three pharmacogemonic applications for cancer treatment.
- KRAS test (KRAS = less likely to respond) to ascertain whether cetuximab would be effective in treating colorectal cancer.
- EGFR test (mutation = better response) to ascertain where gefitinib would be effective in treating non-smallcell lung cancer
- T3151 test to check for BCR-ABL1 gene (mutation = less likely) to ascertain if dasatinib is effective against chronic myelogenic leukaemia
73
What are the aims of a nuchal scan?
- Date the pregnancy
- Diagnose major fetal abnormalities
- Diagnose early miscarriage
- Asses risks of Downs syndromes and other chromosomal abnormalities
74
What is considered abnormal nuchal translucency?
Fluid thickness of >3mm
75
What can an abnormal nuchal result indicate?
- Chromosome abnormalities such as Downs, Edwards, Patau, Turners
- Birth defects such as cardiac abnormalities, pulmonary defects, renal defects and abdominal wall defects
- Skeletal dysplasia
76
What are the different types of prenatal tests?
- Non invasive: Ultrasound or MRI
- Minimally invasive: Maternal blood test, cfDNA test
- Invasive: CVS and Amniocentesis
77
What is the use of a pregnancy ultrasound?
- Early dating
- Nuchal translucency scan
- High level scan be diagnostic to show cardiac or limb defects
78
What is the use of foetal MRI?
Offered if concerned about development of the foetus.
79
What is the use of a maternal serum screening?
Tests maternal markers in the blood to detect increasing risk of foetal trisomy 21, 18 and neural tube defects
80
What is the use of cell-free DNA testing?
Analysing DNA fragments present in maternal plasma (10%-20% comes from the placenta). cfDNA is able to be accurately detected after 9 weeks.
Used to diagnose sex-linked condition by detecting Y chromosome.
81
What are the limitations of non-invasive prenatal testing and diagnosis?
- not possible to distinguish between foetuses in multiple pregnancies
- proportion of cfDNA is reduced in women with high BMIs
- ethical considerations of the results
- invasive tests may still be required to confirm the abnormal results
82
What are benefits of non-invasive prenatal testing?
- number of invasive tests carried out to be reduced
- no increase risk of miscarriage
- less expertise required to carry out test
- can be offered earlier, allowing more time for the woman to make a decision.
83
How is CVS performed? What are the risks? and when is it offered?
Transabdominal or transvaginal sampling of chorionic villus (part of developing placenta).
Risk of miscarriage at 1-2%
Offered at 11-14 weeks
84
How is amniocentesis performed? What are the risks? and when is it offered?
Takes sample of amniotic fluid.
Risk of miscarriage at 1%.
Offered from 16 weeks
85
How can the results from CVS and amniocentesis be analysed?
Karyotype to spot chromosomal abnormality.
| Quantitative Fluorescent PCR
86
What is fat useful for?
- storage of food
- insulation
- support and protection of vital organs
- source of hormones
- sexual signalling
- regulator of immune system
- source of new immune cells
87
Why is not having enough fat a bad thing?
- infertility
- miscarriage
- death from infection
- higher suicide rates
- osteoporosis
88
How is obesity and morbid obesity classified?
Obesity = BMI > 30 kg/m2
| Morbid obesity = BMI > 40 kg/m2
89
Why is it important to take ethnicity into account when using BMI?
Asians have lower BMIs but more body fat %
90
What are the three types of obesities?
Syndromic, monogenic and common
91
What are the factors that cause obesity?
- Lack of physical activity
- Gene variations
- Stress
- High density calorie diet
92
Give an example of a syndromic form of obesity
Prader-Willi syndrome
93
What are the causes of most monogenic forms of obesity?
| What is the most common single gene form of obesity?
They tend to affect appetite.
Fat people have fewer leptin receptors (leptin controls appetite)
The MC4R gene is the most common form of single-gene obesity.
94
What do GWAS show regarding SNPs and obesity?
Only a small proportion of obesity risk can be explained with SNPs (<5%)
95
How can the heritability of common obesity be explained?
- Rare variants
- Epigenetics
- Genomic structural variation
96
List two examples of the application of pharmacogenetics to non-cancer cases
- Variants of the TPMT for the metabolism of the drug 6-mercaptopurine
- Mature Onset Diabetes of the Young (MODY) is often misdiagnosed as T1 diabetes. MODY is treated with metformin instead of insulin.
97
How many SNPs does each person have?
around 3 million
98
How can advances in genomic medicine predict the risk of genomic diseases?
Genomic wide association studies (GWAS) show that many gene variations affect risk of common complex traits.
99
What can direct-to-consumer genetic testing show?
For monogenic diseases:
- carrier status
- detection of rare condition
- determination of later onset disease
For complex diseases:
- risk can be calculated
100
What are the problems of using direct-to-consumer genetic testing for complex diseases?
- limited clinical utility
- may cause undue alarm or false reassurance
- data privacy concerns
- need genetic counselling
- right not to know
101
What are the applications of exome profiles (whole genome profiles)?
- identify novel gene mutations
- identify genetic changes in cancer
- catalogue all genetic variation in population
- drug responses
- disease risk prediction
102
What are the limitations of genetic profiling?
- expensive and time consuming
- right not to know
- protection of data
- equality of access to genetic information
103
What is Pre-implantation Genetic Diagnosis?
PCG is a genetic test carried out on IVF embryos usually to ensure that only embryos free from a particular genetic condition are returned into the woman's womb.
104
What ar the concerns of using PGD?
- discarding of embryos
- slippery slope to designer babies
- eugenics
- spare baby parts
