Abstracts

Rationale: The spectrum of sudden death disorders are unified by a diagnosis eliminating alternative causes of death, such as suffocation, trauma and infection. These disorders include Sudden Infant Death Syndrome (SIDS), Sudden Unexpected Death (SUD), Sudden Unexpected Death in Epilepsy (SUDEP), and Sudden Unexpected Death in the Young (SUDY). Post-mortem analysis and molecular autopsies have revealed presumed causative variants in the same genes indicating an overlap in genetic risk in these disorders. Neuro-cardiorespiratory control has been implicated as a principle pathophysiological cause across the spectrum. The brainstem houses several homeostatic regulatory nuclei, acting to communicate and control cardiac and respiratory systems, which continues to mature ex utero. We hypothesize that lifestage-dependent expression patterns of alternatively spliced gene isoforms in the brainstem cause differential timing of sudden death disorders, despite shared molecular risk factors.Methods: A literature review on SIDS, SUDEP, SUDY, SUD, cardiac arrhythmias, and unexpected, unexplained death yielded 185 candidate genes. Query of public database repositories identified known splice-variants and combination of transcriptome and proteome analysis has identified distinct expression patterns within a subset of high priority molecular diagnostic candidate genes in the developing mouse brain. These spatio-temporal developmental maps will be used in analysis of Next Generation Sequencing data from cases representing the spectrum of Sudden Death.Results: Of the 185 candidate genes, 31% are involved in heart contraction and heart rate, yet only 12% encode voltage-gated ion channels. The Long QT genes (n=13) which are targets of established clinical gene testing because they can cause lethal cardiac arrhythmias, were examined using the Allen Brain Atlas.54% of the genes were expressed in the brainstem while only two of these genes, SCN5A and SCN4B had visible expression in the developing mouse brain across the developmental time points representing the entire sudden death age range (P4-P56). A subset of 64 high interest genes encode over 280 unique isoforms which have different spatio-temporal expression patterns through development Analysis of sudden death genomes revealed patterns of overlapping complexity in known and nominated candidate genes and their splice-variants.Conclusions: The results of this study offer unprecedented insight into the developmental relationships in neuro-cardiorespiratory candidate genes that are implicated in the spectrum of sudden death disorders. For the first time we have identified when, which and what form each gene product is expressed in. This information can further inform preventative diagnostic screening and molecular autopsy.