Direct-to-consumer genetic test results in a clinical setting: a case report

Dr Neeta Tailor is an anaesthetist working at the Royal Gwent Hospital in Wales. Dr Tailor recently treated a friend of Genomes Unzipped members (referred to here as Patient X) who required emergency surgery following some unusual and fairly horrible complications (believe me, I’ve seen the photos!) from wisdom tooth removal. The remarkable thing about this case: prior to surgery the patient volunteered information about her potential drug responses based on her 23andMe profile, including variation in one gene that could have had a profound effect on her response to a standard muscle relaxant. Dr Tailor kindly agreed to write up her experience in this guest post.

For those interested in the genetic details: Patient X’s 23andMe results suggest she is heterozygous for the rs1799807 SNP, which induces an aspartate to glycine change in the BCHE gene and is associated with a substantially prolonged apnea (loss of breathing) following administration of succinylcholine. This is one of three separate mutations in the BCHE gene tested by 23andMe. Although in this case the clinicians had already decided independently to avoid the use of succinylcholine, it’s intriguing to think about how rapidly this type of information could become useful to clinicians – and what steps will need to be taken to ensure DTC genetic testing results are trustworthy enough to justify their consideration in this kind of emergency setting. [DM]

Anaesthesia is classically described as the pharmacologically induced triad of amnesia (memory loss), analgesia (pain reduction) and the loss of muscle reflexes. Patients usually come across anaesthetists during their pre-operative anaesthetic assessment; we are the ones telling you that our job is to pop you off to sleep, although it is usually more complicated than that!

The patient described below works in the world of genetics and invited me to describe her case in order to illustrate how pharmacogenomics and person specific genetic characteristics may affect the choice of general anaesthesia.

A 37 year old woman (Patient X) was booked onto the emergency theatre list on a Sunday morning. The planned operation was incision and drainage of an infected haematoma in the cheek, an unusual complication which had developed quickly over 48 hours following the extraction of a wisdom tooth by her own dentist. By the time she was admitted to hospital, she had extensive facial swelling, not just of her gum, but also the whole of the left side of her face from her forehead to her neck. In addition, she had reduced jaw movement, as well as limited mouth opening of less than one finger breadth. She was also feeling quite unwell having vomited during the night and her blood tests showed raised markers of infection. She was in pain requiring several different types of analgesia.

This presentation in itself poses some difficulty. One of our jobs as anaesthetists involves administering drugs to cause unconsciousness which subsequently requires maintenance of a patent airway using either a mask, an airway device that sits above the vocal cords, or by a tube in the trachea. We usually then maintain unconsciousness using an inhaled volatile anaesthetic via the chosen device.

During this operation we knew we were going to need to share the airway with our maxillo-facial surgery colleagues performing the procedure. To ensure the optimal outcome for all (an anaesthetised patient for us and access to the mouth for the maxfax team), a tube in the trachea was the most ideal option. However, to get to the trachea, we have to get in the mouth and get a good view of the vocal cords and this is where the potential problem could arise.

Sitting an endotracheal tube, or intubation, most commonly involves giving a muscle relaxant; which causes temporary and reversible paralysis of skeletal muscle, including all the muscles that control your breathing. The tube is then positioned via the mouth or nose and connected to a ventilator allowing artificial breathing for the duration of the operation.

The site of action of muscle relaxants is at the neuromuscular junction; the interface between skeletal muscle and the nerve supplying it. The neurotransmitter acetylcholine is released from the nerve terminal and binds to it’s receptor on the surface of the muscle. When enough of these binding sites are occupied, a muscle contraction is initiated. Co-ordinated muscle contraction forms the basis of how we move and breath. There are broadly two groups of muscle relaxants with both acting on the acetylcholine receptor. Non-depolarising muscle relaxants (NDMR) of which there are several in use, compete with acetylcholine for the receptor site to block muscle contraction. NDMR are then metabolised by the body over time and allowed to wear off (most commonly aided by a reversal agent).

The only depolarising muscle relaxant in use is suxamethonium, which has the structure of two back to back acetylcholine molecules. This agent works by binding to the receptor site as before, but this time activating it and causing muscle contraction. It then acts as a block to further acetylcholine molecules until it is eventually broken down by plasma or pseudo-cholinesterase.

The advantage of suxamethonium over NDMRs is that its onset of action is very rapid, working in less than 30 seconds. This allows us to rapidly secure the airway with an endotracheal tube and is most commonly used when there is risk of regurgitation of stomach contents, such as when a patient is unfasted, in pain, having opioid analgesia, has sepsis, or has bowel obstruction. The action of suxamethonium usually lasts between 2 and 5 minutes, which is much less than NDMR which last around 20 minutes or longer. This is beneficial if securing the airway proves difficult, and allows you to get a patient breathing on their own quickly.

Getting back to our patient listed for incision and drainage of an infected dental haematoma, these features of suxamethonium were potentially quite useful. She was in pain, and had been vomiting during the night. She was also highly likely to be difficult to intubate, with a swollen, potentially distorted airway with extremely limited mouth opening. So rapid onset and offset of a muscle relaxant in this case is useful.

Patient X was unlike most patients in that she was aware of a potential problem with an anaesthetic drug, not because she had had a reaction before or had a family member affected by one of the rare inherited reactions, but as a result of her general interest and work in the field of genetics. She had used one of a number of services available to consumers – mainly via the US – where a number of SNPs are analysed and the results made available online from a password-protected website.

Her genotyping suggested that she had genetic variation in her pseudocholinesterase, the enzyme that rapidly breaks down suxamethonium. There are 4 different alleles that make up the genotypes of pseudocholinesterase; the usual and three different abnormal alleles. The overwhelming majority of people are homozygous for the usual genotype, with suxamethonium typically wearing off between 2-5 minutes. However, the remaining may be heterozygous with one usual and one other abnormal allele, or any other combination of abnormal alleles. This can lead to prolonged muscle relaxation with suxamethonium any time between 10 minutes to several hours. Testing for abnormal pseudocholinesterase is a specialist investigation that cannot be carried out at short notice. This test uses an inhibitor of pseudocholinesterase, the normal form being inhibited by 80%. The abnormal forms of psuedocholinesterase are inhibited by varying different level to give a suggestion of what the genotype may be.

The clinical implications of having abnormal pseudocholinesterase are that the potentially beneficial fast offset is not there. This would mean if you failed to intubate the patient, you would potentially be stuck holding a mask over the mouth and nose, and ventilating that way. If you did manage to intubate the patient and complete the operation, they may require continuing mechanical ventilation and thus sedation for a prolonged period of time whilst the muscle relaxation wears off and they start breathing on their own again. The effect of fast onset is unaffected.

As it happens, we had already decided upon an alternative technique of intubation of Patient X due to the extent of the swelling and airway distortion, involving using light sedation to do an awake fibreoptic intubation using a camera via the nose which she tolerated very well and claimed to find a ‘fascinating experience’.

Around 5% of the population will have some degree of prolonged muscle relaxation due to a genetic pseudocholinesterase variant, so it is a condition anaesthetists encounter not infrequently, although a block of several hours is rare. Despite this, it was interesting to see a patient who was able to provide this sort of genetic information without them or one of their family members having had a reaction before. As a clinician, I wonder if knowledge of this type of genetic information will become more common in the future.

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4 Responses to “Direct-to-consumer genetic test results in a clinical setting: a case report”

  • This was a great read. Like Dan said, it’s intriguing to think about the near future when a lot more of such data will potentially be available. Dr. Taylor – as a clinician, what kind of genetic information would you consider in decision making? In this case, you did not have the need to do this, but say you had a) 23andMe data from the patient b) genotypes at all known risk loci for common and rare conditions c) rare and de novo previously uncharacterised functional variants in genes causative for rare conditions (clotting etc). The information in these data range from ‘will cause’ to ‘may have an effect’. Which of these data would you use to 1) inform diagnosis 2) inform treatment options 3) inform of potential complications? And which of these would you advocate as beneficial for patients to have?

  • Again, another reason the FDA needs to regulate these tests that can be used for medical decision making. If it can be used medically, it should be regulated medically.

  • Oh and I wouldn’t trust their reports so much to make solid clinical decisions until the FDA regulates this industry.

    -Steven Murphy MD

  • Dr. Murphy should include a disclaimer with his biased posts that he owns a genetic counseling company. He stands to benefit greatly if the FDA regulates DNA tests by forcing consumers to consult a doctor prior to accessing their results.

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