Opinion

Home > Blog > Blog: Folbigg Inquiry a watershed moment for medical evidence in Australian criminal law

Folbigg Inquiry a watershed moment for medical evidence in Australian criminal law

27th Apr 2023

Initially prompted by a petition to the Governor of NSW signed by more than 90 pre-eminent scientists, clinicians and academics, the Folbigg Inquiry has gone beyond matters of scientific proof and the strength of opinion evidence in unexplained child death, putting genomic testing and its clinical interpretation front and centre in the criminal law and justice system. Notwithstanding that applications for genomic sequencing have been universally upheld in civil litigation in Australia over the last decade, the level of scrutiny that has been applied to a single genomic sequencing result in the Folbigg Inquiry has been unparalleled within the judicial system.

Arguably, the Inquiry and its outcome has the potential to establish a judicial benchmark for genomic testing that:

• ratifies the current standards for the diagnostic reporting of genetic variants by genetic pathologists;
• considers thresholds for testing and reporting relevant to civil and criminal matters; and
• better defines the role of expert evidence in the clinical interpretation of DNA results.

As early as 2004, the English and Wales Court of Appeal identified the hazards of unsubstantiated opinion evidence in child death, overturning the acceptance at first instance of an unfounded figure of one in 73 million as the chance of two unexplained child deaths occurring in a single family.[i] In doing so, the Court recognised the importance of medical expertise, accepting that:

• rare diseases can have a heritable genetic basis, making it more likely that they might recur in some families; and
• proof is dependent on both knowledge and the available diagnostic technology at the time of assessment.

The sprint from genetics to genomics

The history of clinical genetics and DNA testing is paralleled by the immediacy of its application. Advances in engineering and computational analysis matched by an increasing demand from industry, consumers and the healthcare sector have resulted in a rapid acceleration from genetics (the study of genes, heredity and the transmission of traits and disorders from parent to child) to genomics (the study of entire genomes and the interrelationships between genes). In the space of three decades, clinical genetics has moved from a need to recognise and correlate physical patterns of differences as discrete genetic or chromosomal syndromes, to a diagnosis able to be confirmed by a single gene test and, now, to being able to undertake testing that can analyse an entire genome in less than a day, agnostic of prior diagnostic considerations.

To this end, proof of principle for diagnostic genomics and precision medicine has been realised within the last decade. Two pioneering cases demonstrate how a diagnosis can be established from genomic sequencing alone and how this can change the course of a child’s life. Each was driven by parents, predicated on the ground-breaking skills of clinical, computational and research scientists.

An understanding of just how far genetics and genomics has come and what it means to families and clinicians is evident in two books, each written from the perspective of the parents. The first, aptly named Cracking the Code, details a world-first genomic diagnosis in Australian children, while the second, a US counterpart entitled One In a Billion, demonstrates the lifesaving actionability of a genomic diagnosis.

In clinical genomics, the cardinal hypothesis is the likelihood of a genetic basis to the clinical disorder in question. Pragmatically, this assumes the ability to discern critical genetic variants from vast amounts of genomic data; a detailed knowledge of genetic disorders in order to reverse-engineer the process of clinical diagnosis; and the use of strict parameters in both the validation and application of an individual genomic diagnosis.

Central to genomics is genetic pathology, a branch of pathology that is now at the forefront of medical diagnostics and precision medicine. It is genetic pathologists who provide the level of certainty required for accredited genetic and genomic diagnostic test reports, based on rigorous, globally defined, criterion-based consensus standards.

Inquiry validates genomic-testing standards

The Folbigg Inquiry has demonstrated the robustness of genomic diagnostic pathology standards in the judicial setting. It has highlighted where and how differences of opinion might arise and their relation to standards for diagnostic reporting of genetic variants.

The Inquiry highlights an increasingly common situation in which the opportunity for genomic testing or identification of a previously unknown DNA result leads to re-analysis of the individuals and families. While it is always essential to correlate any laboratory finding with what is known about the individual and family (the clinical context), the breadth of genomic testing means it has the potential to not only confirm a diagnosis but to identify a diagnosis that is similar (but not identical) to what was proposed, or in some instances entirely unsuspected prior to testing. Further to this, genomic testing may identify novel genetic variants and even novel genetic disorders for which the prior evidence of causation may be lacking or largely inferred.

The key points of contention in the Folbigg Inquiry are not only in the definitive categorisation of the identified genetic change – as disease-causing rather than a variant of uncertain significance (VUS) – but in understanding how it might affect an individual who inherits the genetic variant. The question at issue is whether the genetic change identified in Kathleen Folbigg and two of her four deceased children may have led to the sudden death of those two children (Sarah and Laura Folbigg).[ii]

The Inquiry has been presented with extensive expert evidence as to the nuanced elements needed to confirm the clinical relevance of a putative genetic diagnosis. When the results fall below a threshold to be deemed ‘pathogenic’ or ‘likely pathogenic’ (disease-causing), then functional testing using computational, biochemical, cellular and animal models is required to assess its clinical relevance and legal causality. Laboratory research has been essential to prove that the DNA change identified in the family is of direct consequence to the basic function of the cell, from which its role in sudden death is then inferred.

Much of the evidence in the Folbigg Inquiry has centred on how the novel previously unreported change in the CALM2 gene and its protein product, Calmodulin2, which was directly proven to deleteriously affect its function in vitro, might give rise to cardiac arrhythmias, based on its destabilising effect on cardiac cell membrane ‘excitability’. This, combined with knowledge from the literature and an International Calmodulinopathy Registry[iii] (<100 cases reported) has been central to the open question of determination of likely pathogenicity versus the more neutral categorisation as a VUS, albeit a highly suspicious one. To this end, it will be interesting to await the Inquiry report to gain a judicial view of the genetic pathology reporting process.

The final step is the interpretation of the genetic findings in the clinical context. It is essential to consider whether the preceding history, circumstances, and events prior to death, such as illness or medication use, for example, might be environmental factors relevant to the triggering of a lethal cardiac arrhythmia. Much of the evidence for this has been in the form of expert opinion. While that opinion has been to a degree discrepant with respect to likelihood, there has been absolute consensus as to the possibility that the inherited CALM2 gene change could have caused the sudden deaths of Sarah and Laura Folbigg.

By way of demonstration that genomic testing can give rise to very open-ended findings, genomic sequencing in Kathleen Folbigg’s two sons, Patrick and Caleb, identified genetic VUSs in both siblings in the BSN gene. This gene, which is associated with early-onset lethal epilepsy when absent in mice, has in the last year been linked to childhood seizure disorders.[iv] The possibility that Patrick had a genetic epilepsy disorder that might have caused a seizure immediately prior to his death was raised in the Inquiry by an expert paediatric neurologist based on the clinical history.

Folbigg Inquiry: A precedent with broad repercussions?

There is little doubt that genomic sequencing is now entrenched in medical litigation and, increasingly, the criminal justice system. What lies ahead, as outlined in my article ‘Genomics and Causation’ in Precedent, is the need for a greater understanding of the merits, limitations and procedural place of clinical genomics diagnostic testing in both civil and criminal matters.

With regard to the Folbigg Inquiry, it is likely that it will not only cement the place of genetic pathology and the expertise of genetic pathologists in litigation but, pending the full findings of the Inquiry and any subsequent judicial review via the Court of Criminal Appeal, it has the potential to establish a precedent that will have broad repercussions for genomics both in the law and as an expected standard in the assessment of unexplained child death, adolescents and young adults.

The ALA thanks Dr Ken Maclean for this contribution.

Dr Ken Maclean is a clinical geneticist in private practice with an active interest in reproductive genetics and its role in child health, genomic testing in litigation and health law. His article, ‘Genomics and causation: A template for every question?’, is published in the March–April 2023 edition of Precedent, the bi-monthly journal of the ALA.

 

 

The views and opinions expressed in this article are the authors’ and do not necessarily represent the views and opinions of the ALA.

Learn how you can get involved and contribute an article. 

Tags: causation Expert evidence Criminal law evidentiary standards Folbigg Inquiry Kathleen Folbigg Precedent Court of Criminal Appeal