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Small Subset of SIDS Cases Linked to Heart Disease in Exome Analysis

NEW YORK (GenomeWeb) – Mutations in known heart disease genes do not appear to be the main genetic contributors to sudden infant death syndrome (SIDS), new research suggests.

Researchers from the US, UK, and Denmark did exome- and targeted sequence analyses on more than 400 infants with SIDS, identifying at least one suspicious, rare, potentially heart disease-related variant in fewer than 13 percent of cases. In contrast to prior studies pointing to genetic heart disease behind as many as one-fifth of SIDS cases, their search led to clinically actionable pathogenic or likely pathogenic genetic heart disease-linked variants in just over 4 percent of SIDS cases overall.

Potentially informative variants in the heart disease-related genes considered did appear to be somewhat more common in infants with mixed-European ancestry or SIDS cases that occurred after four months of age, the team noted today in a Journal of the American College of Cardiology paper. Even so, many cases remained unexplained even after interrogating rare mutations in a broad swath of heart disease-linked genes.

"We now are turning our attention to the genes implicated in other organ systems, like the brain, to determine their potential contribution," co-senior author Michael Ackerman, director of the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, said in a statement. "In addition, we are now exploring other genetic contributions to SIDS, because it is now abundantly clear that most SIDS cases are not due to a single genetic cause."

Prior research, including a study that Ackerman and colleagues published in the Journal of the American Medical Association in 2001, have uncovered mutations in genes behind the inherited heart rhythm condition long QT syndrome and other cardiac conditions in at least a subset of SIDS cases.

Such alterations fit into a so-called "triple-risk model" for SIDS, involving genetic vulnerabilities that interact with external stressors at a critical developmental period, the authors noted. Still, the full suite of genetic contributors to unexpected deaths in infants younger than a year old is unknown.

To get a better sense of the SIDS cases involving genetic heart disease contributors, the researchers used Illumina HiSeq 2000 instruments to sequence protein-coding sequences captured with Agilent exome kits from 427 SIDS cases. After their quality control steps, they were left with data for 419 infants that died of SIDS — a group that included 278 infants of European ancestry and 141 infants with both European and non-European ancestry.

When the team focused on 90 genes implicated in cardiomyopathy and other genetic heard diseases, it saw one or more potentially informative changes in genetic heart disease-associated genes in 21 of the mixed-ancestry cases — just short of 15 percent. An even smaller proportion of European SIDS cases (11.5 percent) had such variants.

Across the complete cohort, 12.6 percent of SIDS cases had at least one such variant, the researchers reported, though that rose to just over 23 percent in infants who lived more than four months. Roughly 4 percent of the infants carried pathogenic or likely pathogenic mutations in the heart disease gene set.

More broadly, the analysis led to 285 ultra-rare variants occurring in more than 46 percent of the SIDS cases. While ultra-rare non-synonymous variants in SCN5A and a handful of other channelopathy genes turned up in just over 3 percent of unaffected controls of European ancestry, for example, the same type of mutations were present in 6.5 percent of European SIDS cases. 

Along with the insights they provide on genetic heart disease-related ties to SIDS, Ackerman said that the SIDS findings "highlight the crucial importance of accurate variant classification to enable proper counseling of surviving family members."

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