“Exceptionally rare” calmodulin mutation could lead to cardiac arrests, Kathleen Folbigg inquiry hears

The building blocks of the human body, and how variations within them could make a person susceptible to cardiac arrest, are central to the new evidence being presented at the inquiry into the convictions of Kathleen Folbigg, the first hearing block of which commenced in Sydney today.

Specifically, it is mutations to a specific gene known as CALM2, which produces the protein calmodulin, which will be discussed by expert witnesses before the inquiry led by former NSW Supreme Court Chief Justice Thomas Bathurst KC, who has powers similar to those of a Royal commissioner.

Counsel assisting the inquiry, Sophie Callan SC, commenced proceedings by giving an overview of the circumstances surrounding the deaths of Folbigg’s four children between 1989 and 1999; the original trial which, in 2003, sentenced her to 40 years in prison (later reduced); and a previous inquiry into her convictions held in 2019.

Callan then delved into the recent scientific research that triggered the enquiry.

That research shows the relationship between a specific variant of the CALM2 gene, known as CALM2 G114R, and the subsequent calmodulin protein it codes for. Folbigg, and her two deceased daughters, have this mutation.

Calmodulin, as cosmosmagazine.com has previously explained, is involved in the regulation of calcium, sodium and potassium, and the heart’s electrical activity.

Callan noted that variations in the CALM gene family (of which there are three genes known as CALM1, CALM2 and CALM3) are very rare, and form part of an emerging field of scientific research.

It was also observed by counsel representing Folbigg, Dr Gregory Woods KC, that the knowledge relating to the CALM genes and calmodulin began emerging only after her conviction in 2003.

But despite several new studies that will be presented to the inquiry, Bathurst impressed upon counsels he would be considering the full range of evidence involved in the case, including diaries and journals written by Folbigg that were used in evidence to secure her conviction.

“I want to make it clear… I can’t confine my attention purely to the scientific evidence, important as it is, I should emphasise,” he said.

Mutations in CALM genes don’t always change calmodulin’s function. When they do, the consequences can be fatal.

If human cells were to build cars, they would create proteins to do it.

This analogy was raised by Callan when describing the role and function of the most basic building blocks of life. Human genes – sequences of DNA nucleotide bases – code for specific proteins that perform specific, complex functions in our bodies.

They are the bricks that build us: they are the components – to borrow the automotive analogy – that keep the car running.

“I can’t confine my attention purely to the scientific evidence, important as it is.”

Thomas Bathurst KC, presiding over the Folbigg inquiry

These proteins are made up of many amino acids, folded together. Each amino acid is coded for by groups of three nucleotide bases, called codons. A variation in any of these codon bases would produce a different amino acid, which in turn would create an altered form of the final protein.

In CALM2 G114R, the mutation at position 114 on the genetic code causes the arginine amino acid to be produced, rather than typical glycine produced at this site.

In her overview, Callan noted “not all genetic variants in the CALM genes will materially change the calmodulin protein or its function, but those that do are capable of causing a cardiac condition…”

That condition, known as calmodulinopathy, is described by another journal article published in December 2018 as a “life-threatening arrhythmia syndrome, affecting mostly young individuals, caused by mutations in any of the [three] genes encoding calmodulin”.

Calmodulinopathy, the article states, can express as Long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) or idiopathic ventricular fibrillation (IVF).

This research was cited by another study by 27 scientists – referred to as the Brohus article – concluded and published after the 2019 Folbigg inquiry. Results published in the Brohus article determined that the CALM2 mutation was likely pathogenic. That means it would be capable of causing calmodulinopathy.

Several senior authors of the Brohus paper, including professors Carola Vinuesa, Peter Schwartz and Michael Toft Overgaard, are scheduled to tender expert evidence on the functional assays conducted as part of that study. A functional assay refers to tests that systematically determine the roles and functions of proteins in a cell.

Last Saturday, Overgaard and his colleague (and wife) Professor Mette Nyegaard, both based at Aalborg University, Denmark, submitted a further functional assay conducted in relation to the G114R variant. They will present evidence to the inquiry on Tuesday; Callan said they will elaborate on variant rarity (irrespective of pathogenesis) in CALM genes, what a mutation to a CALM gene would mean for a person carrying it, and the results of this recent test.

Not all experts due to appear at the 2022 inquiry agree with the Brohus study’s findings.

Clinical geneticist Professor Edwin Kirk from UNSW and paediatric cardiologist and electrophysiologist Professor Jonathan Skinner from The Children’s Hospital at Westmead, who both gave evidence at the 2019 inquiry, are expected to cite limitations in the study.

“[They] observe the functional analyses reported in the Brohus article are not of themselves determinative of whether the CALM2 G114R variant is to be classified as pathogenic, likely pathogenic or a variant of uncertain significance,” explained Callan.

Kirk, along with Dr Michael Buckley and Skinner, also noted in 2019 that in diagnostic settings, functional assays like those used in the Brohus article are “treated with caution” due to cases where false positive results have occurred.

Only one expert was called to give evidence to the inquiry on Monday: Macquarie University Associate Professor Hariharan Raju, a cardiologist who reviewed Folbigg’s cardiac health in February 2019 at the request of her legal team.

Raju noted CALM variants like those identified in Folbigg and her two female children were “exceptionally rare”, as are the heart rhythm disorders known to occur with calmodulinopathy.

He observed in that in the absence of Folbigg’s genetic risk, results of her cardio health test were “not of sufficient abnormality” to be diagnostic of arrhythmic conditions like Long QT or CPVT. However, he added that considering the presence of the variant, it is “certainly plausible” that either of those two conditions could be present in a mild form.

Changes to inquiry as a result of last-minute study submission

The submission of Toft Overgaard and Nyegaard’s new functional assay data will alter the way other experts provide evidence to the enquiry.

Commissioner Bathurst has agreed to adjourn this first hearing block following the presentation of the Danish scientists’ evidence on Tuesday.

This will allow the other expert witnesses including Kirk and Skinner, Schwartz, and Vinuesa and her colleagues Matthew Cook and Todor Arsov time to review the results of the study.

This means the second hearing block, scheduled for 13 February 2023, will be extended to three weeks.

Toft Overgaard and Nyegaard are scheduled to present to the inquiry from 10:30am AEDT on Tuesday.

Further reading:

• Cosmos Q&A: The clash between law and science
• Behind the science of the Folbigg petition
• Folbigg case: timelines compared
• Infanticide vs. inherited cardiac arrhythmias