Authors :
Ian McSalley, MS – Childrens Hospital of Philadelphia
Presenting Author: Shiva Ganesan, MS – Childrens Hospital of Philadelphia
Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia
Rachel Rabin, MS, CGC – NYU Lagone Health
Ingo Helbig, MD – Children's Hospital of Philadelphia
Laura Gould, MSc – New York University Grossman School of Medicine
Orrin Devinsky, MD – NYU Comprehensive Epilepsy Center, NYU Langone Medical Center
Rationale:
Approximately 400 children, ages 1-18 years, die annually in the United States without an identified cause: sudden unexplained death in childhood (SUDC). The genetic contributions to SUDC are under explored and could inform preventive measures.
Methods:
We used exome sequencing (ES) data from 322 trios, consisting of deceased SUDC probands and their parents, from the NYU SUDC Registry & Research Collaborative (SUDCRRC). We performed single nucleotide variant (SNV) calling using GATK and annotation with annovar to identify de novo variants. We used the denovolyzeR statistical framework to analyze the burden of de novo variant in the cohort.
Results:
We identified de novo variants among 244 genetic etiologies. Burden analysis identified variants in 226 genes with significant enrichment against expected frequencies. Of these, 46 genes had existing associations with autosomal dominant conditions. We identified more than one variant on four of these genes: SCN1A, ATXN2, CACNA1C, and RYR2. We also found many genes associated with cardiac-related disorders, including ABCC9,CALM1, KCNH2, and CDH2.
Conclusions: Trio WES analysis of an SUDC cohort revealed a significant over-representation of rare
de novo SNVs. These findings demonstrate involvement of epilepsy- and cardiac-related autosomal dominant monogenic disorders in SUDC, strengthening the genomic understanding of this phenomenon. Our results highlight the need for early genetic screening to identify children at risk and offer vital insights into implicated monogenic conditions.
Funding:
1X01HG014130-01, Genetic Risks of Sudden Unexplained Deaths in Childhood