Folbigg’s life and advances in genetic research

New South Wales will conduct a second inquiry into Kathleen Folbigg’s convictions. At the center of this new investigation is new data on 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 story of the Folbigg affair to advances in scientific understanding of the human genome; how genes code for functional proteins; and research on CALM2which will be presented to the survey.

1952

GENETIC INFORMATION

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

1957

RECEIVER CELLS

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

June 14, 1967

KATHLEEN 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.

January 8, 1969

MURDERED MOTHER

Folbigg’s mother murdered by her father.

1970

CALMODULIN PROTEIN HYPOTHESIS

The hypothetical Hodgkin and Keynes 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

DNA SEQUENCING

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

1983

LOCATION OF GENES

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

1987

WEDDING

Kathleen marries Craig Folbigg.

February 20, 1989

THE FIRST CHILD DIES

Caleb Folbigg dies aged 19 days.

1990

LAUNCH OF THE HUMAN GENOME PROJECT

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

February 13, 1991

SECOND CHILD DIES

Patrick Folbigg dies at the age of 8 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.

August 30, 1993

THIRD CHILD DIES

Sarah Folbigg dies at the age of 10 months.

1997

STUDY OF CALMODULIN

Several 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 the characterization of genes, the function of a gene in the body does not illuminate the clinical relevance of the gene and protein.

1998

CALM2

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

1999

DNA SEQUENCING

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

March 1, 1999

THE FOURTH CHILD DIES

Laura Folbigg dies at the age of 18 months.

2001

FIRST TRY

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

2003

99.9% ACCURACY

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

October 24, 2003

CONVICTION

Folbigg sentenced to 40 years in prison for murder; the period of unconditional release is 30 years, then reduced on appeal to 25 years.

2007

IMPROVED TECHNOLOGY

Improvements in sequencing technology increase genome sequencing time by 70 times.

2008

1000 GENOMES

Launch of the 1000 Genomes project, with the aim of sequencing a large cohort of genomes. Next-generation sequencing dramatically reduces the cost of genome sequencing to US$16 million.

2012

CALM1 STUDIES

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 woman who suffered sudden cardiac arrest at the age of four, but was resuscitated. From there, many studies find correlations between CALM gene mutations and cardiac arrest.

2013

CALMODULIN MUTATIONS

Another study shows that 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 rhythm.

2015

COST EFFICIENCY

The cost of sequencing a complete human genome draft drops to less than US$1,500 and takes 4-12 weeks.

June 10, 2015

FIRST PETITION

New South Wales Governor David Hurley receives a petition to review Folbigg’s convictions. The motion raises a reasonable possibility of his innocence based on forensic findings.

2018

100K GENOMES

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

October 20, 2018

REQUEST

NSW Conviction Inquiry opens.

March 2019

SUBSTANTIVE HEARINGS

Inquest hearings are held and the genomes of Folbigg’s children are sequenced.

May 2019

CAMODULIN REGISTER

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

July 2019

NO REASONABLE DOUBT

The investigating commissioner finds no reasonable doubt about Folbigg’s beliefs. Functional validation of the Folbigg mutation could not be completed before the end of the investigation.

November 2020

INFANT MORTALITY STUDY

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

CALM2 CONFIRMED

A paper, “Infanticide vs. hereditary cardiac arrhythmias”, is published, showing that the mutant variant of CALM2, G114R, was present in both Folbigg children. The authors also report that both male children had mutations in the BSN gene, associated with severe epilepsy in young mice and neurodegenerative disease in adulthood.

March 3, 2021

SECOND PETITION

Petition for Kathleen Folbigg’s pardon presented to NSW Governor Margaret Beazley.

May 18, 2022

SECOND INQUIRY ANNOUNCED

Beazley orders an investigation into Folbigg’s convictions.

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