Question 1

Give a summary of the principal anticipated benefits and challenges that might be expected from widespread clinical genome sequencing.

Accepted Answer

-Benefits. A major benefit will be that the guesswork can be taken out of drug doses (even now, prescriptions for drugs such as warfarin are usually routinely made on a one-size fits all approach; knowing a person's genome sequence will allow more optimal dosing according to the profile of variants in the key drug-metabolizing enzymes). In the case of infectious disease, there is the prospect of rapid-response sequencing of the genomes of individual pathogen strains within hours of disease outbreaks, allowing rapid, innovative responses to epidemics across the globe.
-Challenges. The development of massively parallel genome sequencing has meant that the bottleneck has moved from data acquisition to data analysis. The sheer volume of sequencing data poses challenges for how to both store the data safely and provide a means of rapid ready access to the data while at the sane time maintaining data security and confidentiality.
When even highly trained geneticists struggle to understand current genome sequencing outputs reports, how can we expect physicians to make sense of them? There is a long way to go, and significant challenges in working out out what all the genetic variants mean, which will require very significant development of bioinformatics capabilities allied with functional studies.

Question 2

List four different ways in which a known, specific single nucleotide mutation can be detected within a defined exon.

Accepted Answer

1) Amplification refractory mutation system (ARMS)
2) Oligonucleotide ligation assay
3) Pyrosequencing
4) DNA sequencing

Question 3

What is involved in Southern blot hybridization?

Accepted Answer

DNA samples, almost always genomic DNA samples, are treated with a suitable restriction endonuclease that cleaves the DNA into double-stranded fragments of a manageable size. The DNA fragments are separated according to size by agarose gel electrophoresis (DNA is negatively charged and will migrate towards the positive electrode through the porous agarose gel; small fragments move faster through the gel because there is less frictional resistance than with the larger fragments ).
After electrophoresis, the gel is immersed in strong alkaline solution and the resulting denatured DNA is transferred by capillary action to a nylon membrane that is placed in contact with the gel ("blotting"). The individual DNA fragments become immobilized on the membrane at positions which are a faithful record of the size separation achieved by agarose gel electrophoresis.
Subsequently, the immobilized single-stranded test sample DNA sequences are allowed to associate with labeled single-stranded probe DNA. The probe will bind only to highly related DNA sequences in the test sample DNA, and their position on the membrane can be related back to the original gel in order to estimate their size.

Question 4

What is the basis of the ACCE framework for genetic testing?

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Question 5

Match the disorder
a) to h) with the likelihood that it would be a focus for a genetic procedure listed in i) to vi)

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a) to h) with the...

Question 6

What are the main uses of chromosome fluorescence in situ hybridization in a genetic service laboratory?

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Question 7

Explain the principles underlying target-sequence enrichment from a complex nucleic acid population.

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Question 8

With reference to genetic screening, what is the primary motivation for
a) pregnancy screening,
b) newborn screening, and
c) carrier screening, and what types of disorders are involved?

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Question 9

Concerning preimplantation genetic diagnosis, which, if any, of the following statements is incorrect?
a) It is carried out within the context of assisted reproduction.
b) The analyses always involve genotyping just a single cell and so are technically difficult.
c) Sometime a single blastomere is analysed from the embryo.
d) Sometimes a polar body is analysed to infer the genotype of the embryo.

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Question 10

Give an outline of the different laboratory approaches to testing for aneuploidies and discuss their relative merits.

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Question 11

What are the main applications of Southern blot-hydridization as an assay in a genetics service laboratory?

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Question 12

What is involved in preimplantation genetic diagnosis, and why is it carried out?

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Question 13

What is involved in chromosome fluorescence in situ hybridization?

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Question 14

A genetic test for a marker M was carried out in 500 people affected by disease X and showed that 480 of the affected individuals typed positive for the marker. In a suitably matched set of 1000 healthy controls, just 80 people typed positive for marker.
i) Establish the sensitivity and specificity of the test.
ii) Work out the false positive rate and the positive predictive value
iii) Work out the false negative rate and the negative predictive value.

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Question 15

What is meant by cascade testing?

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Question 16

The triplet repeat-primed PCR assay is commonly used in analysing samples from individuals with unstable trinucleotide repeat expansions. What is involved in this method?

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Question 17

Prenatal diagnosis involves analysing samples originating from fetal cells (either recovered directly from fetal tissue, or from maternal blood samples). What are the aims of these procedures?

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Question 18

Two ethical controversies relating to preimplantation genetic diagnosis involve sex selection and HLA selection. What are the issues involved?

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Question 19

Describe the principles of arrayCGH and its applications in a diagnostic DNA laboratory.

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Question 20

Why is there still a need for conventional karyotyping using chromosome banding techniques?

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Exam 11: Genetic Testing From Genes to Genomes, and the Ethics of Genetic Testing and Therapy