New South Wales will conduct a second inquiry into the convictions of Kathleen Folbigg. At the centre of this new inquiry is new data into the protein calmodulin – specifically one of its coding genes, CALM2 – and a mutated form of the gene known as G114R, which can cause heart arrhythmias in young children.
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.
Alfred Hershey and Martha chase demonstrate DNA carries genetic information, not proteins.
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.
14 June 1967
Kathleen Megan Donovan – later Folbigg – is born in Sydney.
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.
8 January 1969
Folbigg’s mother murdered by her father.
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.
Frederick Danger develops a technique to sequence DNA – this is later used to sequence the first human genome.
James Gisella and team find the location of a gene responsible for Huntington’s disease.
Kathleen marries Craig Folbigg.
20 February 1989
FIRST CHILD DIES
Caleb Folbigg dies aged 19 days.
HUMAN GENOME PROJECT LAUNCHES
It aims to entirely sequence the first human genome with a timeline of 15 years.
13 February 1991
SECOND CHILD DIES
Patrick Folbigg dies aged 8 months.
A technique is developed to genetically test embryos for diseases such as haemophilia while still in the womb.
30 August 1993
THIRD CHILD DIES
Sarah Folbigg dies aged 10 months.
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.
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.
The first fully sequenced human chromosome is released by the Human Genome Project.
1 March 1999
FOURTH CHILD DIES
Laura Folbigg dies aged 18 months.
First draft of the human genome is released by the Human Genome Project, at a cost of US$300 million.
Human Genome Project completed with 99.99% accuracy. It reports around 20,000-25,000 human protein-coding genes.
24 October 2003
Folbigg sentenced to 40 years in prison for murder; non-parole period is 30 years, later reduced on appeal to 25 years.
Improvements in sequencing technology increase genome sequencing time 70-fold.
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.
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.
Another study shows calmodulin mutations are associated with multiple cardiac arrests in infants.
Newly identified mutations in CALM2 are linked to susceptibility to congenital arrhythmia – a genetically inherited irregular heartbeat or heart rhythm.
COST & EFFICIENCY
The cost of sequencing an entire draft human genome drops to under US$1500 and takes 4 to 12 weeks.
10 June 2015
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.
The 100K Genomes Project completes sequencing 100,000 genomes for patients affect by rare diseases or cancer.
20 October 2018
NSW Inquiry into the convictions opens.
Substantive hearings of the inquiry take place and Folbigg’s children’s genomes sequenced.
Calmodulin registry reports that two US children died of the mutation present in the Folbigg girls, Sarah and Laura.
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.
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.
A paper, “Infanticide vs. inherited cardiac arrhythmias”, 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.
3 March 2021
Petition for the Pardon of Kathleen Folbigg presented to NSW Governor Margaret Beazley.
18 May 2022
SECOND INQUIRY CALLED
Beazley directs that an inquiry be conducted into Folbigg’s convictions.