Brohus M, Arsov T, Wallace DA, Jensen HH, Nyegaard M, Crotti L, Adamski M, Zhang Y, Field MA, Athanasopoulos V, Baró I, Ribeiro de Oliveira-Mendes BB, Redon R, Charpentier F, Raju H, DiSilvestre D, Wei J, Wang R, Rafehi H, Kaspi A, Bahlo M, Dick IE, Chen SRW, Cook MC, Vinuesa CG, Overgaard MT, Schwartz PJ. Infanticide vs. inherited cardiac arrhythmias. Europace. 2020 Nov 17:euaa272. doi: 10.1093/europace/euaa272. Epub ahead of print. PMID: 33200177.
Aims: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the deaths, as part of an inquiry into the mother's convictions.
Methods and results: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children.
Conclusion: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths. _______________________________________________________________________
The tabloids in Australia called Kathleen Folbigg a murderer of innocent babies — the nation’s “worst female serial killer.” In 2003, a court sentenced her to 40 years in prison for smothering her four children before each had turned 2.
But all along, Ms. Folbigg has insisted that she is innocent, and that her children were all victims of Sudden Infant Death Syndrome.
Now, 90 leading scientists say they’re convinced she is right. New genetic evidence, the scientists say, suggests that the children died from natural causes, and they are demanding that she be pardoned.
In a petition sent to the governor of New South Wales last week, the group of scientists, which includes two Nobel laureates, called for Ms. Folbigg’s immediate release and an end to the “miscarriage of justice.”
The very public challenge sets up a tense standoff between some of the world’s top medical minds and a criminal court system that rarely overturns convictions. It’s a story of judges putting more weight on the ambiguous musings of a mother’s diary than on rare genetic mutations, and of scientists who are determined to make the legal system respect cutting-edge expertise.
Caught in the middle is Ms. Folbigg, who is now 53. More than 30 years after her first child’s death, her story has not changed, and she maintains that she will be vindicated.
A Troubled Mother and Her Children
Ms. Folbigg’s life has been troubled almost since the moment she was born.
She was just 18 months old when her father, Thomas Britton, murdered her mother in 1968. His wife had walked out on them over a money dispute. He stabbed her on a public footpath in Sydney in a drunken rage.
Roughly 28 years later, Ms. Folbigg wrote in her diary: “Obviously, I am my father’s daughter.”
By that point, in 1996, she had married a miner, Craig Folbigg, had moved to a working-class suburb, Newcastle, a coal capital north of Sydney, and had lost three of her children.
Ms. Folbigg’s first child, Caleb, died on Feb. 20, 1989, at 19 days of age. His death was classified by doctors as Sudden Infant Death Syndrome, or SIDS.
The next child, Patrick, died nearly two years later, at 8 months. He was blind and had epilepsy and choked to death, according to his death certificate.
A baby girl, Sarah, died on Aug. 30, 1993, at 10 months old, and her death was also classified as SIDS. Ms. Folbigg’s last child, Laura, died in March 1999 at 18 months old, with the cause initially listed as “undetermined.”
The deaths seemed at first to be simple, horrific tragedy. But Ms. Folbigg’s husband turned her in to the police after reading one of her diary entries. It said Sarah had left “with a bit of help.”
Ms. Folbigg told the authorities that what she wrote had simply captured the angst and despair of young motherhood and that “a bit of help” referred to her hope that God had taken her baby home.
At her trial, the doctor who had ruled Laura’s death as undetermined, Allan Cala, testified that he had never seen a case of four children dying in the same family. He was admitted as an expert witness, and though he did not present independent data, prosecutors relied on his account to argue that lightning strikes and flying pigs were more likely than four babies dying so young in the same family over a span of 10 years.
“There has never, ever been in the history of medicine any case like this,” one prosecutor said in closing arguments. “It is not a reasonable doubt, it is preposterous.”
The jury agreed. Ms. Folbigg, 35 at the time, was found guilty of the murders of Patrick, Sarah and Laura and the manslaughter of Caleb. She collapsed into tears as the verdicts were read.
The Science That Could Set Her Free
But there was never any medical evidence of smothering, the scientists say — that was one hole in the case. It’s the first thing mentioned in their pardon petition for Ms. Folbigg.
None of the children, they go on to say, were healthy when they died. Laura, the last to die, had been sick with a respiratory infection, and an autopsy later found an inflamed heart.
With those hints in mind, her lawyers asked geneticists to examine the case, searching for a mutation that might explain the family’s experience.
Carola Vinuesa, an immunologist from the Australian National University in Canberra, and another doctor, Todor Arsov, visited Kathleen in prison on Oct. 8, 2018, and received consent to sequence her genome. They both found that Ms. Folbigg had a rare mutation in what’s known as the CALM2 gene.
The genetic defect essentially creates heart arrhythmias that can cause cardiac arrest and sudden death in infancy and childhood.
Only about 75 people in the world are known to have the mutation, Professor Vinuesa said, including some parents without symptoms. But children died in at least 20 of those cases, and in many others, they suffered cardiac arrest.
That was especially true when there were triggers driving up adrenaline — and one known trigger is pseudoephedrine, a drug Laura was taking when she died.
Using blood and tissue samples from all four children, taken shortly after they were born, Professor Vinuesa and Dr. Arsov found that Sarah and Laura both had the same mutation as their mother.
By that point, Ms. Folbigg’s lawyers, who had already exhausted formal appeals, managed to secure a formal inquiry into the case. Professor Vinuesa submitted a lengthy report in December 2018.
But there were signs of resistance. Dr. Cala re-emerged, telling the judge that by the time Laura’s body arrived, after three deaths, you “have to have in the back of your mind, is there something else going on in relation to possible trauma?”
Bob Moles, a law professor at Flinders University, said that the admission of such statements showed a major flaw in Australian justice.
“One of the main problems we have is a willingness of courts to admit scientific evidence that is not really scientific,” he said.
Sensing that the evidence was not being taken seriously, Professor Vinuesa wrote to Peter Schwartz, a world-leading genetic researcher in Milan. He wrote back and said he had been studying a family in the United States with the same mutation, including two children who died from heart attacks.
He sent a letter to the inquiry with his findings. In July 2019, the judge reached a decision. He said that he had considered the scientific evidence but that he had found Ms. Folbigg’s diary quite compelling — and that he had no reasonable doubt about her guilt.
Refusing to Give Up
Frustrated but more determined, the scientists’ network gradually expanded.
Several of the people involved, including Dr. Arsov, submitted their findings to an international peer-reviewed journal. The paper was published in November.
Further research into Caleb’s and Patrick’s genomes has revealed that they had a separate rare genetic variant, which in studies with mice has been linked to early lethal epileptic fits.
In all, 90 eminent scientists have agreed that the medical evidence proves Ms. Folbigg’s innocence. The signatories to the pardon petition include Dr. Schwartz; John Shine, president of the Australian Academy of Science; and Elizabeth Blackburn, a 2009 Nobel laureate in medicine who teaches at the University of California, San Francisco.
“We would feel exhilarated for Kathleen if she is pardoned,” Professor Vinuesa said. “It would send a very strong message that science needs to be taken seriously by the legal system.”
by Damien Cave
Courtesy of a colleague