Hirsch, David; Amor, David --- "Exome and genome sequencing in litigation" [2020] PrecedentAULA 5; (2020) 156 Precedent 14

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EXOME AND GENOME SEQUENCING IN LITIGATION

By David Hirsch and Dr David Amor

‘Next generation sequencing’ (NGS) is the genetic technology that has powered a new wave of scientific discovery over the last decade. More recently NGS has made its way into clinical use, and is starting to have an impact on litigation.

THE MEDICAL PERSPECTIVE

NGS allows the simultaneous sequencing of all genes in the human genome, or of a selected subset of these genes. The main NGS tests that are available clinically are whole genome sequencing (WGS) and exome sequencing (ES). Although WGS is considered the ‘gold standard’ for NGS diagnostics, the clinical uptake of ES is greater due to lower cost and detection rates which are only slightly inferior to WGS. ES does not sequence all DNA but targets the 1 to 2 per cent of the human genome that comprises actual genes and ignores the remainder of the genome, which at present is poorly understood.

It has been demonstrated that NGS testing can identify a specific genetic cause in a range of clinical settings. The likelihood of identifying a cause (diagnostic yield or pre-test probability) varies according to the clinical presentation, from around 5 per cent to greater than 50 per cent.^[1] To date, the clinical presentations associated with the highest yield have been severe intellectual disability, deafness and blindness. Much lower yields have been demonstrated in autism, cerebral palsy and epilepsy, possibly reflecting a more diverse range of causes for these presentations.

NGS testing generates vast amounts of data for analysis, and great care is required to distinguish potentially causative genetic variants from normal variation. Importantly, all individuals carry more than three million genetic variants – points in the DNA sequence that differ from the consensus ‘normal’ sequence – and there is a risk of confusing these with causative variants. Plausible causative variants can be found in every human genome, and so laboratories employ strict criteria before assigning the classification of ‘pathogenic’ to a gene variant.^[2] These criteria incorporate data from medical literature, online databases and computer-based modelling.

Sometimes there is insufficient information to determine whether a particular gene variant is pathogenic or benign, and such variants are classified as ‘variant of uncertain significance’ (VUS). In the future, many VUSs will be reclassified as either pathogenic or benign, as more knowledge becomes available.

Although NGS tests are extremely powerful, it is important to recognise that they do not detect all genetic causes that may be present. As a consequence, NGS tests cannot be used to exclude a genetic cause, although a normal result may reduce the likelihood that a genetic cause is present.

Due to their comprehensive nature, NGS tests also carry a risk of incidental or secondary findings – genetic changes that are not the cause of the patient’s presentation but are relevant to their health.^[3] This possibility can have implications for the person’s ability to obtain certain types of insurance,^[4] as well as having psycho-social implications, and both of these issues are covered routinely in pre-test counselling.

From a practical perspective, NGS tests can now be requested through most clinical genetics services and major hospitals. However, there is no routine government funding, meaning that out-of-pocket expenses may apply. Depending on the exact test and the extent of the analysis, the cost of NGS tests ranges from around $1,000 to $5,000. The time from collection of a blood or saliva sample to release of the result is usually around four months, although some laboratories offer more rapid testing at an additional cost.

Parties are beginning to request NGS testing in litigation settings. A typical example is a medical negligence action involving a child with a neurodevelopmental disorder, such as cerebral palsy, intellectual disability or autism, where there are two competing explanations for causation: brain damage due to foetal hypoxia/ischemia or a pre-existing genetic cause. In this setting, the defendants may request NGS testing in the hope that it will provide definitive evidence of a genetic cause for the disability. Alternatively, the plaintiffs may hope that a normal NGS test will strengthen their argument that the disability was caused by non-genetic factors (although caution is required with this approach because as noted above, a normal NGS result does not exclude a genetic cause). Further, both sides should be aware that the NGS test might identify a VUS, serving only to ‘muddy the waters’.

Another setting in which NGS testing might be requested is following the unexplained death, where competing causes may include a criminal act, medical negligence, an undiagnosed genetic disorder, or just ‘natural causes’.

NGS also poses a potential future litigation risk for doctors for failure to diagnose. Given the power of NGS tests, there are likely many undiagnosed patients who are now potentially diagnosable due to NGS technology, and who may argue in the future that delays in diagnosis were due to the failure of a medical practitioner to order an NGS test.

Finally, in the future, it is likely that NGS testing will be able to uncover genetic explanations for various cognitive, behavioural and personality traits that might constitute a defence for criminal behaviour.

THE LEGAL PERSPECTIVE

Where the physical or mental condition of a party is an issue in litigation, the other party can request, and a court may order, that the first party submit to a medical examination to assess the condition. In NSW, these medical examinations are governed by the Uniform Civil Procedure Rules 2005 (NSW), pt 23, div 1.^[5] Typically a defendant insurer requests that a plaintiff submit to a medical examination and usually this is done without protest. There are consequences for not submitting to a requested test: the plaintiff’s case can be dismissed or stayed.

Defendants have requested blood samples for genetic testing of plaintiffs in many NSW cases, and have been met with protest in some of them. In each disputed case the defendant prevailed and the genetic testing was ordered.

Of those cases, NGS has been the subject of three reported cases so far.^[6] An earlier iteration of genome testing, chromosome microarray, was the subject of two.^[7]

In Zraika (by his tutor Halima Zraika) v Walsh^[8] and Wells by his tutor McGuffog v Hunter New England Local Health District,^[9] the plaintiffs were unborn at the time their mothers were involved in motor vehicle accidents. In Zraika it was alleged the trauma of the accident injured the foetus, leading to hypoxic damage at 25 weeks gestation. There was evidence of a radiological change in brain development that was consistent with a potentially damaging event occurring at that gestation, making the motor vehicle accident (MVA) an attractive causative hypothesis. But there was contrary evidence about whether the MVA could have caused the hypoxic damage.

In Wells it was alleged that in addition to the trauma, the MVA had provoked labour which was later mismanaged leading to avoidable hypoxic injury. The plaintiff did not have ‘classic’ birth asphyxia with hypoxic ischemic encephalopathy, although some contribution of hypoxia to the outcome, at least on the plaintiff’s case, was probable.

In Plowman v Sisters of St John of God Inc,^[10] the defendant conceded that the plaintiff suffered cerebral palsy due to birth asphyxia. However, the defendant argued that a genetic cause may have contributed, at least in part, to the extent of the damage because the plaintiff’s global problems were greater than those normally seen with that degree of hypoxic insult.

In KF by her tutor RF v Royal Alexandra Hospital for Children known as the Children’s Hospital Westmead and Anor,^[11] the plaintiff alleged she suffered avoidable brain damage over a period of six weeks due to an undiagnosed hypoglycaemic condition leading to intermittent seizures. The plaintiff had developmental and language problems that were alleged to have been inconsistent with hypoglycaemic or seizure-induced brain damage. The prospect of a possible genetic cause was sufficient to justify an order for genetic testing.

In McDonald v Ng; McDonald (by his tutor Prudence McDonald) v Ng,^[12] the plaintiff had severe global brain damage involving (arguably) evolving microcephaly and cortical blindness. The plaintiff alleged cerebral palsy due to birth asphyxia, while the defendant categorically denied this as a possible cause.

A number of themes emerge from a review of these cases.

First, an order for a medical examination is discretionary and the invasiveness of the proposed examination and patient factors like phobias and distress could, in appropriate cases, mitigate against a particular test. The plaintiff in Plowman unsuccessfully sought to avoid giving blood for genetic testing on the ground of her needle phobia.^[13]

Second, the quantum of the claim is relevant in the exercise of discretion. The decided cases all involved potentially very large damages. In Wells, Johnson J observed that in a small claim discretion may be exercised to refuse an order for a blood test.^[14]

Third, under the NSW rules non-parties to an action cannot be compelled to submit to medical examinations. This is relevant where NGS is sought to explore the cause of a child’s disability because results can be more reliable if the parents are also tested. In Wells, the defendant requested testing of the plaintiff’s mother. She was the plaintiff’s tutor for the claim, and it was argued that as such she was a party and therefore could be compelled to give a sample of her own blood. Justice Johnson refused the defendant’s application.

In McDonald, however, Harrison AJ acceded to the defendant’s request that the plaintiff’s mother provide a blood sample. The argument raised in Wells about non-parties not being compellable to submit to medical examinations does not appear to have been raised in McDonald. Even so, an interesting point arises where a parent has their own claim for ‘nervous shock’ arising from the injury to their child. In that case, the parent is not the party with the alleged genetic disability, but testing their blood may be relevant to determining their child’s genetic inheritance and hence their own ‘nervous shock’ claim.^[15]

Next, there should be evidence disputing the plaintiff’s contention as to causation. None of the decided cases were straightforward and with the exception of Plowman, where hypoxic brain injury was accepted but the extent of the damages was in dispute, the defendant categorically denied that any alleged negligence was causally relevant to the injury. In the MVA cases, for example, the defendant argued that trauma could not have caused the plaintiff’s injuries; in the cerebral palsy cases the defendant argued that the nature and/or extent of the disabilities were unlikely to be due to hypoxia; and in the hypoglycaemia/seizures case the defendant contended that the plaintiff’s injuries did not fit the pattern of either. In short, all of the genetic testing cases involved hotly contested causation issues.

Finally, the central issue in all of the decided cases was the sufficiency of evidence needed to justify the order for genetic testing. The cases make it clear that the proposed test must be shown to have ‘the capacity to throw light on the issues in the proceedings’.^[16] This is a very low threshold indeed.

In KF and McDonald the plaintiffs argued that the genetic testing sought was still experimental and its capacity to determine causation was questionable. It was contended that the defendants were on a fishing expedition. Further, it was argued that allowing genetic testing was an invitation to embark on a long and complex excursion into the limitations of this emerging science that was unlikely to lead to anything definitive, and result in delay, cost and confusion.

The courts were unconcerned about these matters. The legal test is not whether the genetic testing had a reasonable prospect of definitively answering the causation question; it was sufficient that the test could shed light – however dim – on the issue.

This was explored in Wells, where it was contended that the defendant’s evidence in support of NGS was insufficient to justify the test. In that case, the defendant relied on expert opinion which cited two articles that presented findings on the utility of NGS in finding a genetic cause for two specific types of disability. One article dealt with a study of children with profound intellectual disabilities. Of 371 study participants, 369 had IQ scores below 60 and only two had scores between 60 and 70. In Wells, the plaintiff’s IQ was around 90. The plaintiff argued that the study was not relevant to him. The other article concerned children diagnosed with speech apraxia. The plaintiff in Wells did not have this condition, so it was argued that this article was not relevant to him, either.

Justice Johnson accepted that the plaintiff might have a point, but it did not shift the expert’s stated opinion on the utility of NGS (although the expert might have some explaining to do in cross-examination). His Honour considered that in an interlocutory application, where the expert was not required for cross-examination, it was neither the time nor the place to look too deeply into this issue.

‘It is important to keep in mind that the Court is not purporting to determine the proceedings at this stage even on a type of preliminary basis. The test to be applied is one of adjectival relevance, namely whether there is a possibility that the medical examination will shed light on an issue in the proceedings, being the important issue of causation of the Plaintiff’s disabilities.’^[17]

WHAT’S AHEAD

Genetics is an evolving branch of science. In future, the capacity of NGS to shed a more meaningful light on causation will doubtless increase. It is true that at this stage, and for the foreseeable future, NGS can provide strong evidence of genetic abnormality in a very small number of cases and can provide only very limited information, of questionable forensic value, in many more. Even a normal result does not exclude a genetic abnormality.

It is also true at this stage, and absent a change of attitude at the appellate level for the foreseeable future, that it is very easy for defendants to require plaintiffs to submit to NGS. The test of ‘adjectival relevance’ is so low that the mere possibility that NGS might shed some light – even if that light is weak and diffused – on the causation issue is sufficient.

It seems that the thrall of genetics has gripped the imagination of the courts, as it has everyone else. There is, we believe, a deference to science such that to deny it the chance to explore some possible connection between a plaintiff’s physical or mental condition and their genetics would invite a charge of judicial Luddism.

But we should be cautious about letting science have its way whenever a defendant wants to conscript it. Justice Ipp observed that ‘as geneticists and medical practitioners constantly warn, the ethical and legal difficulties that will arise from this novel area of human endeavour are infinite and are as yet unfathomable’.^[18]

No NGS testing case has gone to trial yet in Australia. When one does, we can expect vigorous arguments about what it all might mean. What is the persuasive value of a test where the result would be, in most cases, that a genetic abnormality is unproven but still possible? It is well known that what is possible in science may be elevated to probable in the mind of a judge. As stated by Herron J:

‘It may be, and probably is, the case that medical science will find a possibility not good enough on which to base a scientific deduction, but courts are always concerned to reach a decision on probability and it is no answer, it seems to me, that no medical witness states with certainty the very issue which the judge himself has to try.’^[19]

It awaits to be seen how the courts will decide causation in cases where the plaintiff’s case falls a little outside of medical orthodoxy.

Those familiar with the international consensus statement on the cause of cerebral palsy^[20] will know that it was designed at the height of the ‘insurance crisis’ to reject birth asphyxia as a cause of cerebral palsy in all cases that failed to meet its strict and sometimes unachievable criteria. Still, plaintiffs have been successful at times, even where the consensus statement criteria were not strictly met, because the weight of the evidence pointed to birth asphyxia and there was no credible alternative cause.

In these cases, one can now expect defendants to require the plaintiff to submit to NGS testing. The results may show some genetic abnormality of unknown significance. Could this be enough to persuade a judge that the plaintiff has not made out their case? Will the plaintiff have to negate the possibility of a genetic cause of their cerebral palsy? What if they can’t – because nobody can?

Another situation may arise where a plaintiff alleges an injury like depression was caused by negligence. Could a defendant require the plaintiff to submit to NGS testing to explore the possibility that the plaintiff was genetically predisposed to depression and would probably have suffered depression later in life anyway, thus reducing damages on Malec v JC Hutton Pty Ltd^[21] principles?

There is a real risk that defendants could abuse NGS testing knowing that a request for this was unlikely to be successfully resisted, throwing delay, confusion and risk in the plaintiff’s way and increasing the prospects of a cheaper settlement.

CONCLUSION

The reach of the science of genetics currently exceeds its grasp, but this does not appear to be a legal impediment to the conscription of NGS testing into the litigation arena. While geneticists appreciate the limitations of this important emerging field, it waits to be seen how judges will manage the uncertainties in any particular case. It seems clear, though, that they will soon get the opportunity to do so as NGS testing of plaintiffs becomes more common and the ability of plaintiffs to resist testing less likely.

David Hirsch is a barrister at Second Floor Selbourne Chambers, Sydney. PHONE [phone] EMAIL [e-mail].

David Amor is Lorenzo and Pamela Galli Chair in Developmental Medicine at University of Melbourne and a clinical geneticist at Royal Children’s Hospital Melbourne. EMAIL [e-mail].

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^[1] K Retterer et al, ‘Clinical application of whole exome sequencing across clinical indications’, Genetics in Medicine, Vol. 18(7), 2016, 696–704.

^[2] S Richards et al, ‘Standards and guidelines for the interpretation of terpretation of sequence variants: Joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology’, Genetics in Medicine, Vol. 17(5), 2015, 405–24.

^[3] SS Kalia et al, ‘Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): A policy statement of the American College of Medical Genetics and Genomics’, Genetics in Medicine, Vol. 19(2), 2017, 249–55.

^[4] M Otlowski et al, ‘Genetic testing and insurance in Australia’, Australian Journal of General Practice, Vol. 48(3), 2019, 96–9.

^[5] Similar although not identical provisions exist in most states. Practitioners should consult the applicable rules of court.

^[6] Zraika (by his tutor Halima Zraika) v Walsh [2014] NSWSC 1774; McDonald v Ng; McDonald (by his tutor Prudence McDonald) v Ng [2018] NSWSC 1050 (McDonald); Wells by his tutor McGuffog v Hunter New England Local Health District [2018] NSWSC 1877 (Wells).

^[7] Plowman v Sisters of St John of God Inc [2014] NSWSC 333; KF (by her tutor RF) v Royal Alexandra Hospital for Children known as the Children’s Hospital Westmead and Anor [2010] NSWSC 891 (KF).

^[8] [2014] NSWSC 1774.

^[9] [2018] NSWSC 1877.

^[10] [2014] NSWSC 333.

^[11] [2010] NSWSC 891.

^[12] [2018] NSWSC 1050.

^[13] It is now possible to undertake NGS testing using a saliva sample.

^[14] Wells, [104].

^[15] In McDonald, the mother had a nervous shock claim. The reason why she was required to provide a blood sample in these circumstances was not explained. This argument was not raised.

^[16] Hamilton v State of New South Wales [2013] NSWSC 1437, [51].

^[17] Wells, [100].

^[18] Harriton (by her tutor) v Stephens [2004] NSWCA 93, [347] referred to in KF, [61] and Wells, [45].

^[19] EMI (Australia) Ltd v Bes [1970] 2 NSWLR 238, 242 (per Herron CJ). See generally the discussion by Spigelman CJ in Seltsam Pty Ltd v McGuiness [2000] NSWCA 29, [93]–[96].

^[20] A Maclennan et al, ‘A template for defining a causal relation between acute intrapartum events and cerebral palsy: International consensus statement’, British Medical Journal, Vol. 319, 1054–9.

^[21] [1990] HCA 20.