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SIDS Exomes Reveal Disruptive Mutations in Skeletal Respiratory Muscle Contributor

NEW YORK (GenomeWeb) – New research suggests that disruptive mutations in the voltage-gated sodium channel gene SCN4A — which codes for a protein called NaV1.4 involved in skeletal respiratory muscle contraction — are over-represented in infants who suffered from sudden infant death syndrome (SIDS).

Following from prior research implicating NaV1.4 defects in a range of muscle-related conditions, including breathing lapses or vocal cord spasms in infants, researchers from the UK and the US did a case-control study involving nearly 300 SIDS cases and more than 700 unaffected controls of matched European ancestry, focusing on suspicious SCN4A alterations in case and control exomes.

In the process, the team detected rare, functionally disruptive changes to SCN4A in 1.4 percent of the SIDS cases considered. Such mutations did not turn up in unaffected infants. The results appeared online yesterday in The Lancet.

"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," co-author Michael Hanna, a clinical neurology researcher at the University College London, said in a statement. "However, more research will be needed to confirm and fully understand this link."

There has been ongoing debate over potential contributors to SIDS. In a study published in the Journal of the American College of Cardiology earlier this month, an international team considered the role of heart disease genes in SIDS — an analysis that uncovered pathogenic or likely pathogenic mutations in heart disease-related genes in around 4 percent of the cases considered.

The same JACC analysis uncovered hundreds of ultra-rare variants in coding sequences from SIDS cases, including an apparent over-representation of rare, non-synonymous mutations in SCN5A and other cardiac channelopathy genes in SIDS-affected infants of European ancestry.

For their new study, Hanna and his colleagues used the Illumina HiSeq 2500 instrument to sequence protein-coding sequences captured with Agilent SureSelect exon enrichment kits in samples from 427 SIDS cases in the UK or the US, along with 729 population-matched controls.

The team focused its subsequent analyses on 278 cases and 729 controls with white European ancestry and sufficient data quality, uncovering rare variants in SCN4A in 2 percent of the SIDS cases and 1 percent of controls. Just one SIDS-affected infant had a rare variant in one of the 90 inherited cardiac disease genes considered — an alteration in SCN5A that co-occurred with a gain-of-function variant in SCN4A.

The variants found in the SIDS cases were vanishingly rare, based on comparisons with Exome Aggregation Consortium data, the researchers reported. And their functional expression experiments, done using a patch clamp heterologous expression system in HEK293 cells, indicated that four of the six rare SCN4A variants identified in SIDS cases were functionally disruptive. In contrast, none of the SCN4A variants from ancestry-matched controls appeared capable of disrupting the function of the NaV1.4 protein.

In the SIDS cases, the authors explained, rare SCN4A variants "are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function." If so, they added, "dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths."

Still, Hanna cautioned that "[w]hile 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."

In a related commentary article, University of California, Los Angeles physiology researcher Stephen Cannon noted that there is "compelling" evidence that SIDS cases involve an over-representation of variants that may disrupt SCN4A channel function.

"A crucial subject for future research is to determine whether laryngeal and respiratory muscles are especially susceptible to even mild disruption of sodium channel function during the first year of life, thereby causing apnea and an increased risk for SIDS," Cannon wrote.