Timeline compared: Kathleen Folbigg’s life and genetic research advances

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

In this timeline, Cosmos compares the history of the Folbigg case against advances in scientific understanding of the human genome; how genes code for functional proteins; and the research into CALM2, which will be presented to the inquiry.

1952: Genetic Information

Alfred Hershey and Martha chase demonstrate DNA carries genetic information, not proteins.

1957: Receptor Cells

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

1967, 14 June: Kathleen Born

Kathleen Megan Donovan – later Folbigg – is 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, 8 January: Mother murdered

Folbigg’s mother murdered by her father.

1970: Calmodulin Protein Hypothesis

Hodgkin’s and Keynes’ hypothesised receptor is attributed to the calmodulin protein. At this point, genetic sequencing did not exist, and so protein analysis did not shed light on genomics.

1977: Sequencing DNA

Frederick Danger develops a technique to sequence DNA – this is later used to sequence the first human genome.

1983: Locating genes

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

1987: Marriage

Kathleen marries Craig Folbigg.

1989, 20 February: First Child Dies

Caleb Folbigg dies aged 19 days.

1990: Human Genome Project launches

It aims to entirely sequence the first human genome with a timeline of 15 years.

1991, 13 February: Second Child Dies

Patrick Folbigg dies aged eight months.

1992: Genetic testing

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

1993, 30 August: Third child dies

Sarah Folbigg dies aged 10 months.

1997: Study of Calmodulin

Multiple studies refine the molecular function of the calmodulin protein gene family. Calmodulin is found to be a multifunctional protein that binds calcium to help regulate, among other things, the cell cycle and cell division. Like gene characterisation, 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 – that is, the gene was compared to others in its family to estimate small, nucleotide differences. Gene characterisation only infers related genes and doesn’t show the function of the gene, or the clinical consequences of mutations in it.

1999: Sequencing DNA

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

1999, 1 March: Fourth child dies

Laura Folbigg dies aged 18 months.

2001: First draft of the human genome

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

2003: 99.9% accuracy

Human Genome Project completed with 99.99% accuracy. It reports around 20,000-25,000 human protein-coding genes.

2003, 24 October: Conviction

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

2007: Technology improves

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

2008: 1000 Genomes

1000 Genomes Project launches with aim to sequence a large cohort of genomes. Next-generation sequencing dramatically lowers the cost of genome sequencing to US$16 million.

2012: CALM1 study

Study shoes that mutations in CALM1, a close relative gene of CALM2, can lead to sudden cardiac arrest. The subject of this study was a 23-year-old female who had experienced a sudden cardiac arrest at age four, but had been resuscitated. From this point, many studies find correlations between CALM gene mutations and cardiac arrest.

2013: Calmodulin mutations

Another study shows calmodulin mutations are associated with multiple cardiac arrests in infants.

2014: New mutations

Newly identified mutations in CALM2 are linked to susceptibility to congenital arrhythmia – a genetically inherited irregular heartbeat or heart rhythm.

2015: Cost and efficiency improvements

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

2015, 10 June: First petition

NSW Governor David Hurley receives a petition for review of Folbigg’s convictions. Petition raises a reasonable possibility of her innocence based on forensic pathology findings.

2018: 100K genomes

The 100K Genomes Project completes sequencing 100,000 genomes for patients affect by rare diseases or cancer.

2018, 20 October: First inquiry opens

NSW Inquiry into the convictions opens.

2019, March: Substantive hearings

Substantive hearings of the inquiry take place and Folbigg’s children’s genomes sequenced.

2019, May: Calmodulin registry

Calmodulin registry reports that two US children died of the mutation present in the Folbigg girls, Sarah and Laura.

2019, July: No reasonable doubt

Commissioner of Inquiry finds no reasonable doubt to Folbigg’s convictions. Functional validation of the Folbigg mutation could not be completed before the end of the inquiry.

2020, November: Infant mortality study

A research team led by Stephen Kingsmore from the Rady Children’s Institute for Genomic Medicine in San Diego (US) estimate infant mortality due to genetic disease is between 10 and 21 percent, but treatment guidelines only covered 70% of the diseases. They suggest that genomic sequencing of infants may help lower mortality.

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

A paper, “Infanticide vs. inherited cardiac arrhythmias” by lead researcher Malene Brohus, is released, showing the mutant variant of CALM2, G114R was present in the two female Folbigg children. The authors also report the two male children had mutations in the gene BSN, associated with severe epilepsy in young mice and neurodegenerative disease during adulthood.

A petition co-signed by 90 eminent scientists calling for Folbigg to be pardoned is presented to NSW Governor Margaret Beazley.

2022, 18 May: Second inquiry called

Beazley directs that an inquiry be conducted into Folbigg’s convictions.

2022, 14 November: Second inquiry commences

The second inquiry into Folbigg’s convictions opens in Sydney before former chief justice of the New South Wales supreme court Tom Bathurst KC. There, Danish professors Michael Toft Overgaard – a senior author on the Brohus article – and Mette Nyegaard, present results of a functional assay into the gene variant CALM2 G114R, finding this variant inadequately performs its regulatory role in heart cells due to compromised binding to calcium and sodium receptors. As a consequence, they argue the variant, which was inherited by Sarah and Laura Folbigg from their mother, would result in cardiac arrythmia. Due to the last-minute submission of the results, the remainder of the hearing is adjourned until February.

2023, 13 February: Inquiry resumes

Bathurst hears from remaining senior authors involved in the Brohus article, professors Todor Arsov, Matthew Cook and senior authors professors Carola Vinuesa and Peter Schwartz. Other internationally-renowned cardiologists and geneticists appraise the work of the Brohus article, with most agreeing that the G114R variant has the potential to be disease-causing.

Other experts in psychology, neuroscience, forensic pathology and paediatrics are called to present evidence relating to other aspects of the case. Neurologist-turned-MP Monique Ryan proposes epilepsy as a cause of death in Patrick Folbigg. Psychiatric and psychological experts determine Folbigg’s diaries – used in her conviction – should be interpreted through the lens of maternal grief, rather than admissions of guilt.

2023, April 26: Final submissions

Counsel assisting the inquiry delivers its final submission to Bathurst, suggesting that “on the whole” the evidence presented during hearings casts a reasonable doubt over Folbigg’s guilt, a view supported – with some qualifications – 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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