Twenty years after she was convicted of killing her four children, Kathleen Folbigg has walked free.
The pardon hinged on key scientific and medical evidence presented at an inquiry that began last year.
The most stunning was the finding that a rare genetic condition that only occurs in one in 35 million people could have caused the deaths of Sarah and Laura.
The finding that an underlying neurogenetic epilepsy could have caused Patrick's death led to the conclusion that three of the four Folbigg children could have died of natural causes.
These findings cast doubt on the assumption that eldest son Caleb was also killed by his mother.
Along with expert opinion that Ms Folbigg's diaries were not evidence that she killed her children, it was enough to convince retired New South Wales chief justice Tom Bathurst KC, who led the latest inquiry, that there was reasonable doubt.
A rare variant
Genetic testing revealed the presence of a mutation (known as CALM2-G114R) in the calmodulin 2 gene in Ms Folbigg, and her daughters Sarah and Laura.
Her sons Caleb and Patrick did not carry the mutation.
The CALM2 gene generates the calmodulin protein, which is essential for keeping the heart beating.
Jozef Gecz, professor of human genetics at the University of Adelaide, said the essential role of calmodulin means the protein is so "protected", that any mutations in the gene are rare and will have serious consequences.
"Once you tamper with it, you introduce a problem and potential explanation why the heart may fail," he said.
There are 20,000 genes in the DNA of all humans and the three calmodulin genes are in the top 15 that have stayed essentially unchanged throughout evolution.
Calmodulinopathy, the name given to the abnormal heart rhythm caused by calmodulin gene mutations, affects just one in 35 million people.
That means that on average, there would be no other families with calmodulinopathy in Australia.
So far, cases have only been recorded in 135 patients worldwide.
Mutations in the calmodulin genes can be life-threatening and are very often lethal in children.
While these calmodulin gene mutations are extremely rare in the population, they are not rare in the Folbigg family.
Every individual inherits two copies of each gene, on a paired set of chromosomes, one from each parent.
Melanie Bahlo, a statistical geneticist at Melbourne's Walter and Eliza Hall Institute of Medical Research, said it was not like the same variant appeared twice, randomly, in Kathleen Folbigg's daughters.
"For her children, the probability of getting that variant is half. It's like a coin toss," she said.
"All four of her children could have gotten that variant."
The mutation discovery could not have been made in 2003, when Ms Folbigg was found guilty of killing her four children.
The bioinformatics revolution
Professor Gecz said the field of human genetics since 2003 has undergone nothing short of a "revolutionary transformative change".
The complete human genome DNA sequence was published in 2000, and the reference gave scientists a blueprint to compare individuals against.
"The first reference genome cost short of $3 billion. But you fast forward in 2010, we started to do it routinely for a few thousand dollars," he said.
In 2012, the first mutations in the calmodulin gene were identified and in 2019 an inquiry into Ms Folbigg's convictions was launched.
DNA came from an internal cheek sample from Ms Folbigg, frozen cell samples from the autopsies of Patrick and Sarah, and 20-year-old cardboard with the heel prick samples taken from Caleb and Laura when they were born.
From these samples, the genome of five Folbiggs was sequenced and analysed.
Two teams of scientists were given the job of interpreting the raw DNA sequence data, using the powerful bioinformatics computing that was then available.
One team concluded the calmodulin gene mutation in Kathleen, Sarah and Laura was "likely" to cause disease while the other team found that its significance was "uncertain".
Former chief judge of the District Court Reginald Blanch, who led the 2019 inquiry, preferred the expertise and evidence of the latter team, and concluded that the evidence "reinforced" Ms Folbigg's guilt.
Whether the calmodulin gene mutation could cause the deaths of Laura and Sarah needed further investigation.
A link between the mutation and the deaths
An international group of scientists that included Professor Bahlo investigated the effects of the Folbigg family's calmodulin mutation by making a mutant protein and looking at its effects in a petri dish.
They published the data in 2021, prompting 90 scientists around the world, including two Australian Nobel Laureates, to petition the governor of NSW to pardon Ms Folbigg.
The experiments showed the mutant calmodulin affected how calcium moved in and out of cells, and these effects were associated with two serious cardiac abnormalities.
Calcium is important in making the heart contract.
Also important was the finding that the mutant calmodulin gene had a similar effect in laboratory experiments as a mutation in the calmodulin 3 gene.
That mutation was discovered in an American boy who died suddenly at age four and his sister who had a cardiac arrest while riding on a carousel at age five.
Professor Gecz said the nature of the calmodulin variants, together with the nature of the fatal cardiac events they have caused in other individuals, was compelling.
"To me, it was kind of a no-brainer, that this was a very good explanation for at least the two girls," he said.
Ten of the 14 cardiogenetic experts involved in the inquiry agreed that the CALM2 mutation was "at least a reasonably possible case" of the girls' deaths.
The ones who disagreed said the possibly fatal effect of the CALM2 mutation on Sarah and Laura did not fit with Ms Folbigg's apparently normal cardiology profile.
Incomplete penetrance
Cardiology investigations have not found evidence of heart problems in Ms Folbigg.
Professor Bahlo said this could characterise a phenomenon called "incomplete penetrance", where some people with a mutant gene have a serious outcome and some don't.
"This is very well documented, there are literally thousands of such examples," she said, citing a variant in the ApoE4 gene that is associated with dementia.
The inquiry heard of an example in a family where five children inherited a mutant calmodulin gene from their mother, four had cardiac arrests or died suddenly, but the fifth child and the mother had no symptoms.
While the inquiry was ongoing, scientists in Canberra identified another gene mutation, REM2, common to all four of the children, but not Ms Folbigg.
That means the children inherited that variant from their father, Craig Folbigg, who has not provided a sample for his DNA to be sequenced.
The REM2 mutation is much less rare than CALM2 — 18 per cent of the population carry it.
The REM2 gene mutation also affects calcium movement in cells.
Professor Peter Schwartz from Italy told the inquiry the combination of CALM2 and REM2 mutations was like "lighting the fuse in a barrel of dynamite" in Sarah and Laura.
"The girls had a double hit, as if they had two mutations, not one. The combination of maternal and paternal DNA has represented a lethal cocktail," he said.
Laura was also found at her death to have had myocarditis, an inflammation in the heart muscle, which the experts said could have caused her death.
That leaves the deaths of Caleb and Patrick.
Lightning strikes multiple times
Patrick, the Folbiggs' second child, had a life-threatening seizure that hospitalised him four months before he died.
He had 15 fits over the next two days and another two the following month, and his sight was affected.
Several experts, including paediatric neurologist Monique Ryan, now the federal member for Kooyong, told the inquiry it was possible that Patrick died of a different genetic disorder.
"He had an uncontrolled seizure disorder, was refractory to medication and it's more likely than not that it caused his death," Professor Ryan told the inquiry.
Counsel assisting the inquiry, Sophie Callan SC, said that in prosecuting Ms Folbigg, the crown had relied on the fact that all four children died in similar circumstances, which meant it was unlikely they were coincidental.
They also reasoned that Ms Folbigg had a tendency to lose control and smother her children.
Explanations for how Patrick, Laura and Sarah may have died from natural causes undermined this reasoning.
That cast doubt on her guilt over Caleb's death.
Professor Bahlo said it was understandable to question how one family could have not one, but two rare diseases.
She published a study last year on a German family that had two devastating rare conditions that were transmitted from one generation to the next and knew of at least one other family in a similar situation.
"There are literally dozens of cases where lightning has struck multiple times," she said.
Professor Bahlo said the benefit of the doubt was there.
"That's the key thing, I guess, for the law. And we are very confident that this is the cause," she said.
"And that means, yeah, she should not be in jail.
"That's the bottom line."
