Genetic sciences and sudden infant death syndrome

We all know how scientific understanding of genetics can influence drug development and is leading to amazing new treatments. But there has been a major story in the news headlines in recent weeks showing how genetic science and knowledge of genetic diseases can affect lives in other ways.

In 2003, Kathleen Folbigg was sentenced to 40 years in prison (later reduced to 25 years) for the manslaughter of one of her children and for the murder of her other three children over a 10-year period. She was accused of smothering the babies, who all died suddenly between the ages of 19 days and 18 months.

In June 2023, a full pardon was signed and she was released due to revelations brought about by genetic research. As part of an investigation into the case, scientists were asked to investigate whether there could be a genetic cause for the children’s deaths.

The research team sequenced the entire genomes of the mother and the children. All four children were found to have unusual genetic mutations. The mother and the two girls had a novel and functional calmodulin variant CALM2 G114R that could have caused sudden cardiac death. The two male infants carried rare biallelic missense variants in the BSN gene, which has been linked to lethal early-onset epilepsy in mice when knocked out. The researchers say more research into these variants will be needed.

Do we know for sure that these genetic defects led to Sudden Infant Death Syndrome (SIDS) in babies and that the mother was not responsible for it? No, but it creates reasonable doubt, which is what led to her release.

The Australian Academy of Sciences acted as an independent scientific adviser to the inquiry. In a press conference, Chief Executive Anna-Maria Arabia said: “We call for legislative reforms such that the legal system can be more sensitive to science. Above all, we need new and emerging science to be able to inform decision-making. Science must inform decisions wherever they are made, including in the justice system.

There is so much we don’t know about SIDS (sometimes known as cot death) and the topic can be controversial. There have been several cases where mothers have been found to be murderers and sent to prison after the sudden death of a child (if you’re interested in this topic, look into the UK cases of Angela Cannings, Sally Clark and Trupti Patel). In the UK and other countries, some prosecutors apply the Meadows Law: one sudden infant death is a tragedy, two is a suspect and three is homicide until proven guilty.

Increasingly, it is being realized that genetic factors may be involved in SIDS. According to an article published by Siri Opdal and Torleiv Rognumm, a mutation or polymorphism is unlikely to be the predisposing factor in all cases of SIDS. However, it is probable that there are SIDS genes operating as a polygenic inheritance that predisposes newborns to sudden infant death, in combination with environmental risk factors. For genetically predisposed newborns, a combination of, for example, a mild infection, a prone position during sleep and a warm environment can trigger a vicious cycle with a death mechanism.

Discovering these genetic mutations is not an easy task. An article published by Christine Keywan and colleagues observes: Understanding the genetic factors that predispose some babies to SIDS is a fundamentally difficult task. In most medical disciplines, a biological condition is first discovered and thoroughly described before a genetic cause is successfully identified. However, in SIDS genetic research the reverse has been the case: genetic testing and research have helped elucidate plausible mechanisms of death in SIDS. SIDS is understood to be a heterogeneous condition and we have only a rough understanding of which conditions contribute to the mechanisms responsible for its fatal outcome.

In 2019, Hannele Ruohola-Baker, professor of biochemistry at the University of Washington School of Medicine, led a multi-institution study on mitochondrial trifunctional protein deficiency, a potentially fatal cardiac metabolic disorder caused by a genetic mutation in the HADHA gene . Infants with the mutation cannot metabolize the lipids found in milk and can die suddenly from cardiac arrest. At the time of publishing the paper, Ruohola-Baker said: There is no cure for this. But now there is hope, because we have found a new facet of this disease that will innovate generations of new small molecules and engineered proteins, which could help these patients in the future.

However, designing medicines suitable for newborns is always a significant challenge, but the life sciences industry has shown that the future may be closer than we think. It wasn’t that long ago that gene editing and cell therapies were considered a blue-sky academic job that would never work in real life. Eventually, there may be suitable treatments that can help prevent SIDS. And most importantly, early screening is needed so that children at greatest risk of sudden death can be identified.

In another example of positive breakthroughs, researchers at Childrens Hospital Westmead reported the identification of a potential biochemical marker in 2022 that could detect babies at risk for SIDS.

Slowly, progress is being made.

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