Image: The SureSelect All Exon kits are the most widely used target enrichment solution for exome sequencing (Photo courtesy of Agilent Technologies).
Sudden infant death syndrome (SIDS) is the unexpected death of a seemingly healthy infant. It is the leading cause of post-neonatal infant death in high-income countries and accounts for 2,400 deaths per year in the USA alone and around 300 in the UK.
Death from SIDS commonly occurs at two to four months of age. Although the cause of death is unknown, several intrinsic and extrinsic risk factors have been identified, including prematurity, male sex, prone sleeping position, and bed sharing. A failure to rouse and respond appropriately to a life-threatening hypoxic event is considered to be a common final pathway.
A large team of scientists working with the University College London (London, UK) studied two cohorts of children of Caucasian European ancestry 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.
The investigators used tissue from each group and their genes were analyzed to identify whether they had a mutation in the Sodium Voltage-Gated Channel Alpha Subunit 4, (SCN4A) gene, and to confirm whether the mutations affected the cell surface receptor that the gene codes for. Whole exome sequencing for both cases and controls was done using 1.5 to 3 μg of genomic DNA and in the UK sequencing was performed using the Sure Select XT Human All Exon v5 Target Enrichment System. DNA libraries were prepared according to manufacturer's protocols and 100 base pair paired end sequencing was performed on the Illumina HiSeq 2500 platform.
The authors found general mutations in the SCN4A gene in six of the 284 infants who died, and in nine of the 729 controls. Specific 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 conclude that the disruptive variants are over-represented in this group, and could indicate 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.
Michael Hanna, MD, FRCP, a professor of Clinical Neurology and a senior author of the study, said, “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. 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.” The study was published on March 28, 2018, in the journal The Lancet.
University College London