Characteristics of sudden unexpected death syndrome (SUDS) patients.

<p>Characteristics of sudden unexpected death syndrome (SUDS) patients.</p

Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome

<div><p>Introduction</p><p>Sudden unexpected death syndrome (SUDS) is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES) to investigate the cause of SUDS in Thai sudden death victims.</p><p>Materials and methods</p><p>A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015. The coding sequences of 98 SUDS-related genes were sequenced using WES. Potentially causative variants were filtered based on the variant functions annotated in the dbNSFP database. Variants with inconclusive clinical significance evidence in ClinVar were resolved with a variant prediction algorithm, metaSVM, and the frequency data of the variants found in public databases, such as the 1000 Genome Project, ESP6500 project, and the Exome Aggregation Consortium (ExAc) project.</p><p>Results</p><p>Combining both autopsy and molecular autopsy enabled the potential identification of cause of death in 81% of the cases. Among the 25 victims with WES data, 72% (18/25) were found to have potentially causative SUDS mutations. The majority of the victims had at a mutation in the <i>TTN</i> gene (8/18 = 44%), and only one victim had an <i>SCN5A</i> mutation.</p><p>Conclusions</p><p>WES can help to identify the genetic causes in victims of SUDS and may help to further guide investigations into their relatives to prevent additional SUDS victims.</p></div

Characteristics of sudden unexpected death syndrome (SUDS) patients.

<p>Characteristics of sudden unexpected death syndrome (SUDS) patients.</p

Potentially causative variants in SUDS.

<p>Potentially causative variants in SUDS.</p

Characteristics of each patient.

<p>Characteristics of each patient.</p

A summary of all sudden death victims.

<p>Autopsy identified the cause-of-death in 14 victims. The remaining 25 sudden unexplained death (SUDS) victims were investigated with whole exome sequencing.</p

A summary result of whole exome variant filtering.

<p>(SNV = single nucleotide variants, MAF = minor allele frequency).</p

Potential pathogenic variants in each patient.

<p>Potential pathogenic variants in each patient.</p

HLA class II genotypes of 32 affected individuals with disseminated opportunistic infection and positive anti- IFN- γ autoantibody (case group).

<p>HLA class II genotypes of 32 affected individuals with disseminated opportunistic infection and positive anti- IFN- γ autoantibody (case group).</p

HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies

<div><p>Recently a newly identified clinical syndrome of disseminated non-tuberculous mycobacterial diseases (with or without other opportunistic infections in adult patients who were previously healthy, has been recognized in association with an acquired autoantibody to interferon-gamma. This syndrome is emerging as an important cause of morbidity and mortality, especially among people of Asian descent. Trigger for the production of this autoantibody remains unknown, but genetic factors are strongly suspected to be involved. We compared HLA genotyping between 32 patients with this clinical syndrome, and 38 controls. We found that this clinical syndrome was associated with very limited allele polymorphism, with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02. Odds ratio of DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02 were 7.03 (95% CI, 2.18–22.69, P<0.0001, 9.06 (95% CI, 2.79–29.46, P<0.0001), 6.68 (95% CI, 2.29–19.52, P = 0.0004), and 6.64 (95% CI, 2.30–19.20, P = 0.0004), respectively. Further investigation is warranted to provide better understanding on pathogenesis of this association.</p></div