By Jean Balchin 02/04/2018

A case-control study in the UK and USA has found that rare genetic mutations associated with impairment of the breathing muscles are more common in children who have died from sudden infant death syndrome (cot death) than in healthy control children. Published recently in The Lancet, this study seems to indicate that there exists a possible genetic element of the disorder.

Sudden infant death syndrome (SIDS) is the unexpected, and often inexplicable death of a seemingly healthy child. Also known as cot death, it is the leading cause of post-neonatal death in high income countries. However deaths are rare, and an individual baby’s risk is low. There are around 300 cases of SIDS each year in the UK, 2,400 in the USA, and it occurs most frequently within the first three months of a baby’s life.

The mechanisms behind SIDS are unclear, although it is evident that certain factors can increase the risk. Babies being unable to regulate their breathing is thought to be an important component. SIDS is more common in male babies and those born prematurely. Putting babies to sleep on their back, and not sleeping in the same bed as a parent is known to reduce the risk of SIDS.

These genetic mutations are found very infrequently in controls, and are typically found in fewer than five people in every 100000. This study however 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.

Clearly, more research is necessary to understand the link identified between these mutations and SIDS. Further research is also necessary to ascertain whether drug treatments might be suitable. The authors stressed that this is not the sole cause of sudden infant death syndrome, and other elements also play a part.

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

Mutations in the SCN4A gene are associated with a diverse array of genetic neuromuscular disorders, including as periodic paralysis, myotonia, myopathy, and myasthenic syndrome. Life-threatening pauses in breathing may also occur, as well as spasms of the vocal cords that make breathing or speaking temporarily difficult.

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

Tissue from each group was used and 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.

It was found that there existed general mutations in the SCN4A gene in six of the 284 infants who died, and in nine of the 729 controls. However, 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. The authors thus conclude that the disruptive variants are over-represented in this group, potentially indicating a genetic element of sudden infant death syndrome.

The authors suggest that this may increase susceptibility to sudden infant death syndrome in some cases as the cell receptor becomes more commonly used. During this period, the mutation could potentially leave 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 correct their breathing, cough or catch their breath in response.

However the authors stress that the gene mutation is probably not the sole cause of death, and safe sleeping measures for babies are still necessary to ensure safety.

Moreover, given that SCN4A variants are found in some adults with neuromuscular disease, it is evident that SCN4A mutations are not always lethal. According to corresponding author Professor Michael Hanna, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK:

“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.

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.”

Co-author Dr Michael Ackerman, Mayo Clinic, USA, says:

“This international collaborative UK-USA study provides interesting new evidence for a possible link between respiratory muscle sodium channel dysfunction and SIDS; further research is needed to confirm these findings and to evaluate any potential clinical relevance.”


Limitations of this study include the fact that it only included white people of European ancestry; results will need confirmation in other ethnicities. Moreover, given that the information from children who died from sudden infant death syndrome was anonymised, there was limited other clinical data and other family members could not be tested. Evidently, prospective studies are necessary to confirm the link between the mutation and sudden infant death syndrome.

Writing in a linked Comment, Dr Stephen Cannon, UCLA, USA, says:

“Sudden infant death syndrome (SIDS) remains a leading cause of infant mortality, despite a steadily decreasing incidence since the 1990s. The reasons for this decline are debated, but it could be due to methodological reasons (eg, changes in reporting or advances in diagnosis of specific diseases) or a reduction of risks, such as an increase in supine sleeping position for infants, as advocated by the Back to Sleep campaign. A better understanding of the causes of SIDS is needed to identify infants at high risk and to develop interventions and guidelines that will prevent SIDS for all infants… Overall, the evidence is compelling that variants of SCN4A with disruption of channel function are overrepresented in SIDS.”