Folbigg pardoned: a case history and genetic advances

Kathleen Folbigg was pardoned by the Governor of New South Wales and released.

In this timeline, Cosmos compare the Folbigg case story to advances in scientific understanding of the human genome; how genes code for functional proteins; and search into CALM2which will be submitted to the inquiry.

1952: Genetic Information

Alfred Hershey and Martha Chase demonstrate that DNA contains genetic information, not proteins.

1957: Receptor Cells

Hodgkin and Keynes suggest that there may be receptors in cells that move calcium, based on a previous hindsight experiment, this role can now be attributed to the protein calmodulin.

1967, June 14: Kathleen was born

Kathleen Megan Donovan – later Folbigg – was born in Sydney.

1968: Nobel Prize

Marshall W. Nirenberg, Har Gobind Khorana and Robert W. Holley win the Nobel Prize in medicine for their interpretation of the genetic code and its function in protein synthesis.

1969, January 8: Mother murdered

Folbiggs’ mother murdered by his father.

1970: Calmodulin protein hypothesis

The receptor hypothesized by Hodgkin and Keynes is attributed to the protein calmodulin. At this point, genetic sequencing did not exist and therefore protein analysis did not shed any light on genomics.

1977: DNA sequencing

Frederick Danger develops a technique for sequencing DNA which is later used to sequence the first human genome.

1983: Finding Genes

James Gisella and his team find the location of a gene responsible for Huntington’s disease.

1987: wedding

Kathleen marries Craig Folbigg.

1989, February 20: the first child dies

Caleb Folbigg dies at the age of 19 days.

1990: Launch of the Human Genome Project

It aims to fully sequence the first human genome with a 15-year history.

1991, February 13: the second son dies

Patrick Folbigg dies at the age of eight months.

1992: genetic testing

A technique is being developed to genetically test embryos for diseases such as haemophilia while they are still in the womb.

1993, August 30: the third child dies

Sarah Folbigg dies at the age of 10 months.

1997: Calmodulin study

Numerous studies refine the molecular function of the calmodulin protein gene family. Calmodulin is found to be a multifunctional calcium-binding protein to help regulate, among other things, the cell cycle and cell division. Like gene characterization, the function of a gene within the body does not illuminate the clinical relevance of the gene and protein.

1998: CALM2

The CALM2 gene is characterised, i.e. the gene has been compared to others in its family to estimate small nucleotide differences. Gene characterization infers only related genes and does not show the function of the gene or the clinical consequences of mutations in it.

1999: DNA sequencing

The first fully sequenced human chromosome is released by the Human Genome Project.

1999March 1: the fourth child dies

Laura Folbigg dies at the age of 18 months.

2001: First draft of the human genome

The first draft of the human genome is released by the Human Genome Project, at a cost of $300 million.

2003: 99.9% accuracy.

Human genome project completed with 99.99% accuracy. It reports about 20,000-25,000 human protein coding genes.

2003, October 24: Convicted

Folbigg sentenced to 40 years in prison for murder; the non-parole period is 30 years, later reduced on appeal to 30 years and 25 years of non-parole.

2007: Technology gets better

Improvements in sequencing technology increase genome sequencing time 70-fold.

2008: 1000 genomes

The 1000 Genomes project is launched with the goal of sequencing a large cohort of genomes. Next-generation sequencing dramatically reduces the cost of genome sequencing to $16 million.

2012: CALM1 study

Study Shoes that mutations in CALM1, a close relative of CALM2, can lead to sudden cardiac arrest. The subject of this study was a 23-year-old woman who suffered sudden cardiac arrest at age four, but she was revived. From this point, many studies find correlations between CALM gene mutations and cardiac arrest.

2013: calmodulin mutations

Another study shows that calmodulin mutations are associated with more cardiac arrests in newborns.

2014: New mutations

The recently identified mutations in CALM2 are linked to susceptibility to congenital arrhythmia, a genetically inherited irregular heartbeat or heart rhythm.

2015: Improved costs and efficiency

The cost of sequencing an entire draft human genome drops to less than US$1500 and takes 4 to 12 weeks.

2015, June 10: First petition

NSW Governor David Hurley receives petition for Folbiggs’ convictions to be reviewed. The petition raises a reasonable possibility of his innocence based on the forensic pathology findings.

2018: 100K genomes

The 100K Genomes project completes the sequencing of 100,000 genomes for patients with rare diseases or cancer.

20 October 2018: opening of the first investigation

NSW Inquiry into convictions opens.

2019, March: substantial hearings

Substantive inquest hearings are held and the genomes of the Folbiggs children are sequenced.

2019, May: Calmodulin registry

The Calmodulin Registry reports that two US children died from the mutation present in the Folbigg girls, Sarah and Laura.

2019, July: no reasonable doubt

The commissioner of inquiry finds no reasonable doubt about Folbiggs’ convictions. Functional validation of the Folbigg mutation was not completed until the end of the investigation.

2020, November: Infant Mortality Study

A research group led by Stephen Kingsmore of the Rady Children’s Institute for Genomic Medicine in San Diego (USA) estimates that infant mortality due to genetic diseases is between 10 and 21%, but the therapeutic guidelines only covered 70% of diseases. They suggest that genomic sequencing of newborns may help reduce mortality.

2021, March: CALM2 confirmed in Folbigg women; new petition to the governor of NSW

An article, “Infanticide Against Hereditary Cardiac Arrhythmias” by lead researcher Malene Brohus, is published, showing that the CALM2 mutant variant, G114R was present in the two Folbigg girls. The authors also report that the two sons had mutations in the BSN gene, associated with severe epilepsy in juvenile mice and neurodegenerative disease during adulthood.

A petition co-signed by 90 prominent scientists asking for Folbigg’s pardon is presented to NSW Governor Margaret Beazley.

2022, 18 May: the second investigation convened

Beazley orders an investigation into Folbigg’s beliefs.

2022, November 14: the second investigation begins

Second inquest into Folbiggs convictions opens in Sydney before former New South Wales Supreme Court Chief Justice Tom Bathurst KC. There, Danish professors Michael Toft Overgaard, senior author of the Brohus paper, and Mette Nyegaard present the results of a functional analysis on the CALM2 gene variant G114R, finding that this variant inadequately fulfills its regulatory role in cells heart failure due to impaired binding to calcium and sodium receptors. As a result, they argue that the variant, inherited by Sarah and Laura Folbigg from their mother, would cause heart arrhythmia. Due to the last minute presentation of the results, the remainder of the hearing is adjourned in February.

February 13, 2023: the investigation resumes

Bathurst hears from the remaining senior authors involved in Brohus’ paper, Professors Todor Arsov, Matthew Cook, and Senior Professor Authors Carola Vinuesa and Peter Schwartz. Other internationally renowned cardiologists and geneticists evaluate the work of Brohus’ article, with most agreeing that the G114R variant has the potential to cause disease.

Other experts in psychology, neuroscience, forensic pathology, and pediatrics are called upon to present evidence relating to other aspects of the case. Neurologist turned Congresswoman Monique Ryan proposes epilepsy as the cause of death in Patrick Folbigg. Psychiatric and psychological experts determine that Folbiggs’ diaries used in sentencing him should be interpreted through the lens of maternal grief, rather than an admission of guilt.

2023, April 26: final submissions

The inquest counsel delivers his final statement to Bathurst, suggesting that overall the evidence presented at the hearings casts reasonable doubt as to Folbiggs’ guilt, a view supported with some reservations by the NSW Director of Public Prosecutions.

2023, June 5: Folbigg pardoned

Kathleen Folbigg receives an unconditional pardon following Bathurst’s finding that there is reasonable doubt as to her guilt.

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