Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

Abstract

In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

Molecular autopsy for sudden death in Japan

“…Osawa et al showed that variations in the novel QT interval determinant NOS1AP may be involved in the occurrence of SIDS 49 . Similarly, we previously performed molecular autopsy to investigate sudden infant death 33,35,37,39,50,51 .…”

“…Takahashi et al also reported a case of sudden death due to Marfan syndrome caused by an FBN1 gene variant 58 . These studies were performed using Sanger sequencing, and currently, NGS-based studies are being reported in Japan 37,39,51,[59][60][61][62][63][64][65][66][67][68][69][70] .…”

“…Case 3: Sudden arrhythmogenic death in sudden infant death 51 A 3-month-old female infant died while sleeping. External examination revealed no injury and macroscopic and microscopic examinations revealed no abnormalities.…”

I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy

“…Most studies used target sequencing and exome sequencing with next-generation sequencing. However, problems arise when comprehensive exome sequencing detects many genetic variants, and the interpretation becomes difficult [5]. The mechanism at the molecular biological level is important.…”

Postmortem Identification of Genetic Variations Associated with Sudden Unexpected Death in Young People

“…NGS can detect more variations than direct sequencing and most genetic variants are classified as variants of uncertain significance (VUS) 5) , and thus multiple variations in an individual make interpretation of pathogenicity difficult. 6,7) Molecular analyses, including knock-in mouse experiments and recombinant cell experiments, as well as family pedigree analyses, are important methods for exploring this pathogenicity. However, these methods are difficult to perform during routine postmortem practice: the former is both cost-and effort-consuming, while the latter is difficult to realize, especially in sudden death cases, because there is often a lack of familial and clinical information.…”