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Sudden Unexpected Death Syndrome Exome Search Leads to Pathogenic Variants

NEW YORK (GenomeWeb) – A team from Thailand has used exome sequencing to search for explanations in sudden unexpected death syndrome (SUDS) cases in that country.

The researchers assessed post-mortem samples from more than two dozen seemingly healthy Thai individuals who died suddenly between January and August 2015, largely focusing their analysis on 98 genes implicated in SUDS in the past. The results, published online today in PLOS One, revealed apparently pathogenic mutations in nearly 75 percent of those tested. In particular, they found that eight of the SUDS cases included mutations affecting TTN, a gene coding for a titin protein in striated muscle function.

Senior author Warangkna Boonyapisit, a researcher at Mahidol University, and her co-authors noted that a "significant proportion" of Thai SUDS cases could be traced back to inherited genetic alterations, "especially in young individuals with no abnormal structural heart diseases by autopsy."

Although many sudden deaths are eventually attributed to cardiac arrhythmias or other known conditions, the researchers explained, a significant proportion of SUDS are not linked to a particular condition or structural heart problem. Such cases are over-represented in parts of Southeast Asia, they added, prompting a more detailed genetic look at SUDS cases in Thailand.

The team considered detailed autopsy data for 42 SUDS cases, which involved individuals aged 18 to 55 who died unexpectedly at home from January 2015 to August 2015. The investigators ruled out SUDS in 15 individuals who had signs of heart disease, pneumonia, or other known conditions, and excluded two more samples from exome sequencing stage of the study due to poor quality or non-Thai ancestry. All but one of the remaining individuals were male and some 88 percent died in their sleep.

After capturing protein-coding sequences with Agilent SureSelect kits, the researchers sequenced the exomes with Illumina HiSeq 4000 instruments, comparing variant patterns and frequencies with those found in exome sequences from 162 unaffected individuals from the Thai population. Their analysis uncovered almost 112,000 SNPs and 10,154 small insertions and deletions across the full exomes of the individuals with SUDS.

When the team considered sequences from 98 genes suspected of influencing SUDS, it saw 801 SNPs and 67 indels, including 28 variants from 18 of the cases that appeared to be pathogenic based on predicted functional effects and ClinVar classifications.

Along with mutations in TTN, the researchers identified potentially causative mutations in genes such as KCNH2, CACNB2, KCNQ1, and TPM1. They cautioned that the clinical significance of such variants has not yet been explored, but noted that the findings point to exome sequencing as a strategy for narrowing in on promising candidates.

"Genetic investigation by [next-generation sequencing] provides an affordable and powerful diagnostic tool in SUDS," the authors concluded, "and could prevent further loss through family screening and lifesaving management among victims' family members."