CALM2 variants aren’t benign says geneticist; psychologists to assess Folbigg diaries

There are no benign calmodulin variants, or such is the view of the Danish research team whose work has been quizzed at Monday’s resumption of the inquiry into the convictions of Kathleen Folbigg in Sydney.

That inquiry heard professors Mette Nyegaard and Michael Toft Overgaard respond to questions regarding the genetic variant – called CALM2 G114R – they suggest would explain the deaths of Folbigg’s daughters.

Folbigg, convicted in 2003 for the murder of her three youngest children and manslaughter of her eldest, has served 20 years in prison. She’s eligible for parole in 2028.

Toft Overgaard and Nyegaard were the only expert witnesses to present evidence at the opening of the inquiry in November last year, and recapped that evidence in today’s resumption of the hearing.

Nyegaard, a geneticist, discovered the first missense variants – or mutations – to the crucial genes that code for the functional protein calmodulin.

Proteins in the body are coded for by combinations of three genetic bases, called codons. Each codon instructs the production of one of 20 amino acids, which fold together to create unique proteins that perform important biological functions.

A missense variant occurs where a single genetic “base” changes, therefore altering the amino acid produced to form the final protein. 

More: What is calmodulin?

Those variants, Nyegaard and Toft Overgaard suggest, would lead to cardiac arrythmias, which could prove fatal in young children.

They reinforced their view that the G114R variant is likely pathogenic – or disease causing – due to what they observed to be ineffective binding of the protein to the sodium ion channel in heart cells.

The pathogenicity of G114R and whether it could cause the death of Sarah and Laura Folbigg, who possessed this mutation, will be debated among experts at the inquiry.

One known pathogenic gene – G114W – is similar in its structure; Toft Overgaard likened it to G114R. The G114W mutation was found in the DNA of an American girl who died suddenly at age five and her brother, who was resuscitated from a cardiac arrest at age four.

Just as the pathogenic “W” variant replaces glycine – the smallest of the 20 amino acids – with tryptophan (the largest), the “R” variant replaces glycine with arginine (the second largest).

Folbigg amino acids
Whereas glycine is the smallest amino acid, arginine (in the G114R mutation) and tryptophan (in the known pathogenic G114W mutation) are the largest. Credit: Image generated with IQmol

This, they suggest, shows the severity by which the mutation impedes calmodulin performing its role.

Where experts differ

One key point likely to be raised during proceedings is disagreement between the Danes and Dr Calum MacRae, a cardiologist from Harvard Medical School and Brigham and Women’s Hospital, US, who will appear later this week.

Counsel assisting the inquiry Sophie Callan indicated MacRae will raise doubts about the pathogenicity of the G114R mutation.

MacRae says there are a numerous non-lethal CALM2 variants.

Nyegaard disagrees, saying her research demonstrates the importance of CALM2 resisting mutation. She told the court in the case of the Folbigg mother and daughters, it has changed, with potentially fatal consequences.

Psychology experts find no reason to suggest Folbigg intent

At the reopening of the inquiry, Callan forecast the likely areas of contention between experts over the next three weeks.

Toft Overgaard and Nyegaard’s research, along with the co-authors of their 2019 study that triggered this inquiry, may be challenged by MacRae and others who take issue with their claim about pathogenicity.

The inquiry will again examine the content of Folbigg’s diaries.

Can the law keep up with science?

Psychology and psychiatry expert evidence will be presented next week. Callan’s summary of these experts suggests none will find the diaries to be an admission of guilt.

Instead, Callan said, they will variously find Folbigg’s writings indicate a grief-stricken woman exhibiting characteristics of depression and post-traumatic stress.

The inquiry continues tomorrow with evidence from professors Todor Arsov and Carola Vinuesa, who were co-authors with Toft Overgaard and Nyegaard of the study into G114R.

More on the Folbigg inquiries

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