BIO3204 - Molecular Diagnostics 2 Assignment

Assignment Task

Question 1

A 12-month-old boy is taken to the family doctor. He is falling behind on major motor development milestones and is exhibiting tachypnoea whilst feeding. The child’s mother informs the clinician that she had a maternal great-aunt who had two sons who died in late infancy / early childhood from heart and muscle weaknesses. The boy was found to have dilated cardiomyopathy after an echocardiogram was performed and the physician diagnosed the boy with mild general muscle weakness. The physician ordered a FBC, E/LFT, CK and urine M/C/S. The returned results indicated that the child had a neutropenia and acidic urine (pH 3.9). Additionally, CK concentrations were within normal limits.

a) Based on the clinical information provided and the family history, what is your diagnosis and what is this disease an example of? 

b) What is the inheritance pattern of this disorder? 

c) What two tests should be requested to confirm your diagnosis?

d) Please state the function of this gene and how mutations in this gene lead to the development of the disease that you have diagnosed this young boy with (i.e. what is the cellular basis of the disease)?

Question 2 

A 33-year-old man was complaining of major fluctuations in appetite, itchy skin, presyncope, constant nausea and easy bruising. He noticed his cuts were slow to heal as well. This feeling continued for weeks, and it was not until he noticed the whites of his eyes started turning yellow that he visited his doctor. His doctor ordered subsequent rounds of pathology which indicated that the young man had type two diabetes mellitus and cirrhosis. The young man was prescribed metformin, was asked to stop drinking alcohol and was sent to a dietician to assist with his nutrition. A few weeks passed and he still was not feeling any better despite being this. His doctor ordered a FBC, E/LFT and iron studies. It was noted that he had high serum iron, ferritin and transferrin saturation, as well as a high haemoglobin.

a) What is a potential diagnosis for this disease and what initial molecular diagnostic test would confirm your diagnosis?

b) The patient has an older brother. His brother is clinically healthy. However, it was recommended that the older brother also be tested for the condition his younger brother has developed. Looking at the results below from a RFLP, which column belongs to the sick patient and which one belongs to the healthy older brother? Please justify your answer.

c) Let us suppose that this man tested negative for the initial molecular diagnostic test that is typically requested with this disease, but all the clinical features did not change, with the exception that the clinician forgot to consider that he was not Caucasian. What would be the most likely gene we would test for given the symptoms? Please briefly justify your answer.

d) What is the mechanism by which a mutation in the above gene leads to the development of this particular disease (i.e. what is the cellular basis of disease)?

Question 3

A 15-year-old woman presented to her physician with easy bruising and severe fatigue. This persisted for about a week. Her physician ordered a FBC and E/LFT. The results returned the following:

a) Based on the above findings, please answer the following:

1. What is your preliminary diagnosis? 
2. What treatment should the clinician commence the patient on?
3. Outline how this treatment works (i.e. its mechanism of action).

The physician requested that flow cytometry be added, however, there was insufficient sample. The physician recalled the patient urgently and requested FISH and a chromosomal analysis. The results of these are shown in the figure below along with the final report.

b) The patient’s clinical picture has not changed, rather the cytogenetic results do not much the clinical picture. Suggest why this may be the case?

Molecular testing was subsequently performed by the lab following the interim results obtained through FISH (listed above). The following result was obtained:

c) Based on these results should your original diagnosis change? Please justify your answer.

d) Please outline how this fusion gene results and the fusion products that occur from these products.

Question 4

A 37-year-old Japanese man presented to an Emergency Department with a non-productive cough that had persisted for two weeks. He did not have pyrexia or dyspnoea, nor did he have a rash or petechiae. He had a history of right hemiparesis, intellectual disability with pica, symptomatic epilepsy which resulted from intracerebral haemorrhage (occurred when the patient was 2 years old), and never smoked or consumed alcohol. His initial vital signs were as follows:

• Blood pressure: 105/55 mmHg
• Heart Rate:70 bpm
• Respiratory rate:18 bpm
• SpO2: 93%
• Body temperature: 36.5°C
• Physical exam (i.e. lymphadenopathy, auscultation of chest, cardiovascular, abdominal and neurological exam: unremarkable (other than the cough)

An X-ray was ordered and so too was a follow-up chest computed tomography. The results are shown below:

The initial pathology results are shown below:

• Haematology
  • Hb: 149 g/L
  • WCC: 8.85 x 10⁹/L with a left-shift noted
• Biochemistry:
  • LDH: 425 U/L (RR: 119-229 U/L)
  • TP: 53 g/L (RR: 65-80 g/L)
  • Alb: 21 g/L (RR: 40-50 g/L)
  • CRP: 91.8 mg/L (RR: < 5>
  • KL-6: 2940 U/ml (RR: < 500>
  • Surfactant protein D: 173.0 ng/ml (RR: < 109>
  • Surfactant protein A: 115.0 ng/ml (RR: < 43>
  • RF, ANA, Immunoglobins were all within normal reference ranges
  • Blood cultures were negative
  • Initial microscopy for acid-fast bacteria was negative and there were no pathogenic organisms identified using general microscopy

The patient had a follow-up fibre-optic bronchoscopic exam, the results of which suggested a normal endobronchial system. A combined bronchoalveolar lavage (BAL)/transbronchial biopsy (TBLB) was performed during this process. The BAL form the right middle lobe was collected and indicated the following:

• Histiocytes - 87%; Neutrophils - 6%; Lymphocytes - 4%; Eosinophils - 3%
• Cultures: Negative

TBLB from the right upper lobe was collected and indicated alveolar septal thickening and collagen-type fibrosis.

These findings assisted the team to diagnose the patient with interstitial pneumonia and treat intravenous levofloxacin (500 mg) once daily, as well as corticosteroid pulse therapy (methylprednisolone [1000 mg]) for three days followed with prednisolone (1 mg/kg/day).

Five days post treatment the patient’s respiratory condition worsened. Non-invasive positive pressure ventilation commenced, and the patient was also given intravenous cyclophosphamide (500 mg). A serum (1-3) β-D glucan concentration was requested and returned a result of 104.3 pg/ml (reference range <6>

Post-mortem examination showed the following:

Given Pneumocystis jirovecii is unculturable, invasive testing is required for diagnosis using the methods listed. The screening tests used are potentially low in specificity and sensitivity and may be subjective in low concentrations of Pneumocystis jirovecii. Hence, a nucleic acid amplification test (NAAT) should have been requested. Your task is to go through this case study and outline four (4) clear points in the case where NAAT could have been requested, as well as a justification as to why for each point.

Question 5

TP53 is the most commonly mutated gene observed in more than 70% of all human cancers. It is not specific to any form of cancer. Mutations can result de novo or they can be inherited. An example of this is shown in the pedigree below:

a) Please answer the following:

1. What is the pattern of inheritance shown in the pedigree and what non-traditional pattern of inheritance is also observed in this pedigree?
2. What complex inherited cancer predisposition disorder is demonstrated by this pedigree? Please explain how you arrived at this conclusion.
3. Please suggest a molecular diagnostic method that could be used to detect a mutation in the TP53 gene and identify three (3) specific mutations within the TP53 gene that can be detected by this method.

b) A common feature of cancer cells is that they can be homozygous for loss-of-function mutations in the TP53 These loss-of-function mutations can often be observed in the gene region that encodes the DNA-binding domain of the protein it encodes for. Please outline how these specific mutations can develop into the observed cancerous phenotype in these cells (i.e. how can mutations in this gene lead to cancer within a cell).

c) If a cell is heterozygous for a mutation that causes the protein TP53 encodes for to bind tightly and constitutively to the DNA of its target genes, then how would this mutation affect the cell cycle? 

d) If the type of mutation described in (c) were to occur, would you expect these cells to be more or less sensitive to the effects of ionising radiation? Why?

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