Medical Genetics MCQs Flashcards
A homozygous nonsense mutation was found in 2 brother with early onset muscular dystrophy. Explain how three other classes of mutation typically result in no protein expression?
a) An Indel mutation which is not multiple of three leads to a change to open reading frame and can lead to the introduction of a premature termination codon upstream of last exon-exon junction, this causes mRNA to be degraded by NMD
b) Mutation affecting splicing, for example an intron is no longer excluded, this leads to changes in the open reading frame which introduces a premature termination codon upstream of last exon-exon junction, leads to NMD.
c) Large deletion causing removal cis elements required for transcription and/or translation
d) Point mutation affecting non-coding regulatory element resulting in no transcription
Point mutation in the transcription start site resulting in no transcription
2) What are the main phases of the cell cycle, and what is happening within the cell in each case?
a) G0 – cells are in the quiescent phase. They are metabolically active but do not undergo cell division (1 mark).
b) G1 – cells are metabolically active and are growing (1 mark)
c) S – DNA synthesis and replication takes place in this phase; the total amount of DNA is double the amount found in a cell in G0 or G1 (1 mark)
d) G2 – Protein synthesis, growth and preparation for cell division occur (1 mark)
e) M – Mitotic phase – cells divide (1 mark)
4) Draw a diagram illustrating the key sequence elements and protein complexes required for constitutive splicing
constitutive sequence elements required include the 5’ splice site (1/2 mark), the 3’ splice site (1/2 mark), the branch site (1/2 mark) and the polypyrimidine tract (1/2 mark). The proteins that bind these sequences are the U1 spliceosomal component to the 5’ donor site (1/2 mark), the U2 spliceosomal protein to the branch site (1/2 mark), the U2AF protein to the polypyrimidine tract (1/2 mark) and the U4/U5/U6 tri snRNP complex to the U1 and U2 snRNPs (1/2 mark).
4) Draw a diagram illustrating the key sequence elements and protein complexes required for alternative splicing
Students should have identified that regulatory regions are present within both introns and exons. Exon splicing enhancers (ESEs) (1/2 mark) and exon splicing silencers (ESSs) are found in exonic regions (1/2 mark) and Intron splicing enhancers (ISEs) (1/2 mark) and intron splicing silencers (ISSs) are found in intronic regions (1/2 mark). The student should have also indicated that ESEs and ISEs bind Serine Arginine (SR) proteins (1/2 mark) and exon splicing silencers (ESSs) and intron splicing silencers (ISSs) usually bind hnRNPs (1/2 mark).The exact placement of motifs is not important.
a) What is the difference between a presymptomatic and a diagnostic test
Diagnostic – when a patient is showing signs of particular disorder, presymptomatic is before a patient is showing signs, predicting what will happen in future
At what age is presymptomatic testing performed and why?
Presymptomatic tests are usually performed after the age of 18
Testing prior to 18 can:
a. Infringe on the child’s future autonomy (they may not want to know) (1 mark)
b. Cause psychological damage growing up knowing that were going to affected by a serious late onset disorder (1 mark)
c. Stigmatisation (being treated differently by family and acquaintances) (1 mark)
c) In what situation would a presymptomatic test ALWAYS be indicated in a person under the age of 18 and give an example?
If the pre-symptomatic test could directly benefit the child by allowing medical or surgical intervention (1 mark)
For example Familial Hypercholesterolemia (diet and statins)
What are the main differences between apoptosis and necrosis?
a) Apoptosis is programmed cell death, necrosis is unprogrammed (2 marks)
b) Apoptosis is physiological (i.e. a normal cellular process) whilst necrosis is pathological (associated with disease) (2 marks)
c) Apoptosis elicits no inflammatory response, whereas necrosis is associated with an inflammatory response (2 marks)
d) Apoptosis is elicited by cellular physiological stimuli such as lack of growth factors or activation of p53, whereas necrosis can be caused by external factors such as viruses, hypoxia, ischemia (2 marks)
Why is a consanguineous relationship more likely to produce offspring with a genetic abnormality?
a) All individuals carry a number of rare, deleterious, recessive mutations (1 mark)
b) When parents are related to each other it increases the chance of both parents carrying the same rare mutation (1 mark)
c) thus there is an increased risk of any offspring inheriting a mutation on both chromosomes (1 mark)
State the componants of a gene, the percentage of the gene and the function?
a) Promoter 0-10%
• A cis-acting regulatory DNA element upstream of a transcription unit which binds RNA polymerase.
b) 5’ UTR
• The untranslated region between the transcription start site and the initiator sequence (usually AUG)
c) Exon 0-10%
• Region of transcript that is included in fully processed mRNA, an exon may be coding and generate transcripts which are translated into protein or non-coding and not be translated.
d) Intron 21-35%
• Region of transcript that is not included in fully processed mRNA, is removed during splicing.
e) 3’UTR 0-10%
• The untranslated region between the stop codon and poly(A) tail.
f) Coding Region 0-10%
• The entire exonic sequence that is translated (i.e. does not include 5’ and 3’ UTR
Describe two potential sources of missing heritability of multifactorial diseases.
rare variants- rare variants with large effect sizes have have not been captured on SNP chips
structural variants not tested for on SNP chips,
epigenetics variants are not tested on SNP chips
epistasis, complex gene interactions are not considered
When counselling a patient about their risk of developing an autosomal dominant disorder what other factors may you need to consider in addition to whether the patient has inherited the disease causing mutation? Explain with examples why these factors affect a patient’s risk of becoming affected by a disorder
a) Penetrance
– Not all disorders are fully penetrant therefore even if a patient has inherited mutation they may not develop the disease (eg Inherited Breast cancer has a penetrance of 50-80%)
b) Anticipation
- When the disease develops at an earlier age in each generation, this important information to impart to the patient (i.e. trinucleotide repeat disorders)
How is variation created during meiosis?
Crossing over- homologous chromosomes exchange genetic material at chiasma during prophase 1
The paternal and maternal chromosomes are randomly sorted due to independent segregation, so the mix of chromosomes is different from cell to cell.
List the components of the promoter and how far each is from the translation start site
GC region: -90
CAAT: -75
BRE: -37
TATA: -25
What are the essential bases at each of the different areas for splicing?
5’ splice site: GU
Branch point: A
3’ splice site: AG
Define SNP
variation of a single nucleotide at a specific locus where each variant is present in at least one percent of the population
Describe the three models for ethics?
- Utilitarian ethics: considers what is best for the majority, used in the NHS
- Code of conduct: considers the ethics of doing your duty
- Virtue ethics considers how does a decent person act, underpins ethical considerations of medical genetics
Describe the four ethical principals upheld in genetic testing?
- Autonomy: the patient has the right to decide their own treatment and decide what happens to them
- Beneficence: must benefit the individual
- Non-maleficence: must not harm anyone
- Justice: genetic testing should be equally available/ accessible to all
what three criteria must be satisfied to have informed consent?
- Disclosure of information
People must be given all the information in order to make the decision however not too much infor: can be overwhelming - Free from coercion (consent must be voluntary)
Mainly relating to the clinician, for example if a family member doesn’t want to get tested but because another member does they change their mind, they then should be tested: people have a right to let themselves be coerced although this should not be by a clinician - Capacity/ competent: in the right position to make informed consent
Capacity/ competence is assessed based of an individuals understanding of specific decisions which need to be made
Assessment only applies to the decision and time
Information must be tailord to the cognitive ability of the individual: for example you have to explain things in a simple way for children compared to an adult or someone with learning difficulties
Describe the 100 000 genomes project?
A UK Government project that is sequencing whole genomes from NHS patients with rare diseases, some common types of cancer, and infectious diseases. Participants give consent for their genome data to be linked to information about their medical condition and health records. The medical and genomic data is shared with third parties including researchers and commercial organisations
