Case Study: The Barnes Family

5BIOM002w2

Medical Genetics in Practice

2020-21

Case Study and Instructions

for CW2

1. Mary – aged 6 months - is the second child born to Paul and Danielle Barnes. Her older brother Jimmy is now 4 years old and very healthy, in fact his parents have to buy age 6 clothes for him. Mary, however, is a different matter. She has worried her parents from the start. Although she took her bottle well she was very slow to put on weight and in her first few months seemed constantly to have cold and a cough.

2. When she was 5 month old Mary was really ill and was admitted to hospital with a chest infection. The nurse commented that her bowl motions were very bulky and offensive, and when her weight and height were plotted on the charts they were on lower centiles then they had been at birth and in her first month. The doctors suspected she might have cystic fibrosis and therefore arranged for her to have a sweat test.

3. The sweat test confirmed the doctors’ suspicion (Na+ level of 87 mmol/l, well above the normal upper limit of 60 mmol/l). The clinical diagnosis came a s complete bombshell to Danielle and Paul. At their request, Mary’s paediatrician arranged for them to see a Geneticist to talk things through.

4. Following the consultation with the Geneticist it appeared that there is no family history of cystic fibrosis or other evident genetic problems. “How can it be genetic, when nobody in either side of the family has ever had it?” Danielle asks.

The Geneticist explains that the pedigree (Mary as proband) is typical of the way Cystic Fibrosis presents in societies where consanguinity is not common.

5. Cystic fibrosis is always caused by mutations in the CFTR gene on chromosome 7. CFTR is quite a large gene. Mutations may be anywhere in the gene. Different patients may have different mutations.

Mary is referred for molecular genetic testing to confirm the clinical diagnosis. Also, molecular testing is needed for advising relatives about their carrier status and for prenatal diagnosis should Mary’s parents consider having more children in the

future.

6. Mary’s DNA was tested and the result shows that she has the p.F508del mutation, also known as delta-F508, in exon 10. Mary is heterozygous for this mutation.

Further analysis reveals that something was different in exons 3 and 14b in Mary’s DNA compared to a normal control. The following changes were identified:

Exon 3: c.368G>A

Exon 14: c.2752-15C>G

Either or both of these may well be non-pathogenic sequence variants

7. Mary’s second and third mutations were not common and required further analysis.

When DNA from Mary’s parents Paul and Danielle was checked, both the p.F508del and c.2752-15C>G came from Paul. The C>G change was in intron 14a, 15 nucleotide before the start of exon 14b.

Mary’s other mutation, c368G>A, did come form her mother. The nucleotide change is within exon 3 and converts the codon for tryptophan 79 (TGG) into a stop codon (TAG).

8. Both Mary’s parents come from quite large families. Their relatives are clearly at high risk of being carriers for cystic fibrosis. Since the mutations present in Paul and Danielle are now known, it is fairly simple for any relative who might so wish, to be tested for these specific mutations.

Because cystic fibrosis mutations are common in the general population, it is also prudent to test for a panel of the commonest mutations, just in case anybody happens to be a carrier coincidentally, having inherited a mutant gene form a different ancestor from the ones who were the source of Paul and Danielle’s mutations.

With reference to the case-study, please write a report (max 2400 words, excluding references) covering the following areas:

• Provide an overarching narrative of the information presented in the case study

• Use your knowledge to describe the genetic basis and clinical presentation of Cystic Fibrosis, with particular emphasis on the molecular mechanistic aspects (from gene structure to protein alteration and effect on function)

• What are the current methods for the clinical diagnosis of Cystic Fibrosis?

• Which specific genetic tests were Mary and her parents referred for? Why were they referred for genetic testing?

• Which type of DNA changes were revealed and how? Were all the different mutations found in their DNAs confirmed to be pathogenic? What is the relevance of this type of investigations?

• Discuss the challenges (cost vs sensitivity) and potential ethical and emotional issues surrounding cascade screening for carriers

• Using your knowledge and critical skills outline what are in your opinion the most valuable current practices and the most promising developments in terms of treatment and therapeutics options for Cystic Fibrosis

Marking Rubric:

• Provide an overarching narrative of the information presented in the case study (10/100)

• What are the current methods for the clinical diagnosis of Cystic Fibrosis? (10/100)

• Which specific genetic tests were Mary and her parents referred for? Why were they referred for genetic testing? (10/100)

• Which type of DNA changes were revealed and how? Were all the different mutations found in their DNAs confirmed to be pathogenic? What is the relevance of this type of investigations? (20/100)

• Discuss the challenges (cost vs sensitivity) and potential ethical and emotional issues surrounding cascade screening for carriers (10/100)

• Correct Referencing (essential)

• Presentation (grammar, spelling, formatting, use of figures, etc.) (essential)

Your report will have to demonstrate in-depth understanding, conceptual integration and criticality.

Your report will have also to demonstrate learning supplementation through judicious selection of reference material and competent use of genetic databases.

Please organise your writing logically and aim at writing clearly and accurately, ensuring descriptions are concise yet cover all relevant details.

Maximum number of words: 2400

The deadline for submission through Turnitin is: Tuesday 13th April 2021 at 1:00 pm

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