Rare genetic mutations associated with impairment of the breathing muscles are more common in children who have died from sudden infant death syndrome, according to a new study led by UCL researchers.

The study, published in The Lancet, suggests a possible genetic element of the disorder, which is also known as 'cot death'.

"Our study is the first to link a genetic cause of weaker breathing muscles with sudden infant death syndrome, and suggests that genes controlling breathing muscle function could be important in this condition. However, more research will be needed to confirm and fully understand this link," said the study's senior author Professor Michael Hanna (UCL Institute of Neurology).

These mutations are very rare, and typically found in fewer than five people in every 100,000. However, the study found mutations of this kind in four of the 278 children who had died of sudden infant death syndrome, compared to none of the 729 healthy controls.

"We think the genetic mutations we found may have contributed to why some of these infants died but are likely to have interacted with other risk factors and would not necessarily be the sole cause of death," said the study's last author, Dr Emma Matthews (UCL Institute of Neurology).

Sudden infant death syndrome is the unexpected death of a seemingly healthy child. It is the leading cause of post-neonatal death in high income countries, but deaths are rare, and an individual baby's risk is low. Typically, it affects children aged between 2-4 months, and accounts for 300 deaths each year in the UK.

The cause of the disorder is unknown, but babies being unable to regulate their breathing is thought to be an important component. Putting babies to sleep on their back, and not sleeping in the same bed as a parent is known to reduce the risk.*

The study looked at the prevalence of mutations in the SCN4A gene which codes for an important cell surface receptor (a skeletal muscle sodium ion channel protein). The expression of this cell receptor in breathing muscles is low at birth and increases over the first two years of life.

Mutations in this gene are associated with a range of genetic neuromuscular disorders and with life-threatening pauses in breathing, and spasms of the vocal cords that make breathing or speaking temporarily difficult.

The study included two cohorts of children who had died from sudden infant death syndrome in the UK and USA, including 278 children overall (84 from the UK and 194 from the USA). All deaths were unexplained after thorough post-mortem investigations. These were matched with 729 adults who had no history of cardiovascular, respiratory or neurological disease.

Their genes were analysed to identify whether they had a mutation in the SCN4A gene, and to confirm whether the mutations affected the cell surface receptor that the gene codes for.

While the study found general mutations in the SCN4A gene in six of the 284 infants who died, and in nine of the 729 controls, mutations that disrupted the cell surface receptor were only found in four of the children who had died of sudden infant death syndrome, and none of the controls.

As the disruptive variants are over-represented in this group, the researchers say this could indicate a genetic element of sudden infant death syndrome.

The mutation could cause the cell receptor to become more commonly used, leaving these children with weaker breathing muscles, and, if an external stressor impacts their breathing (such as tobacco smoke, getting tangled in bedding, a minor illness or a breathing obstruction), they may be less able to catch their breath.

As SCN4A variants are found in some adults with neuromuscular disease, the mutations are not always lethal.

"While there are drug treatments for children and adults with genetic neuromuscular disorders caused by SCN4A gene mutations, it is unclear whether these treatments would reduce the risk of sudden infant death syndrome, and further research is essential before these findings can become relevant to treatment," said Professor Hanna.

"We are very pleased that leading researchers continue to try and identify the cause of SIDS, which leads to the death of around four babies every week in the UK. In the meantime, we urge all parents to continue to follow our safer sleep advice to reduce the risk of SIDS: always place your baby on their back, in their own cot or Moses basket, in the same room as you for all sleeps, day and night," said Francine Bates, CEO of The Lullaby Trust, in a supporting statement.

This study was funded by the Medical Research Council, Wellcome, National Institute for Health Research, British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, Epilepsy Society, National Institutes of Health, and the Mayo Clinic. It was conducted by researchers from UCL, the National Hospital for Neurology and Neurosurgery, St George's University of London and St George's University Hospitals NHS Foundation Trust, Mayo Clinic, Chalfont Centre for Epilepsy, University of Edinburgh, Western General Hospital, Royal Infirmary of Edinburgh, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, Sheffield Children's NHS Foundation Trust, University of Bristol and King's College London.

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