<i>De Novo</i> Mutations in 124 Cases of Sudden Unexplained Deaths in Childhood

Abstract

Background: Sudden unexplained death in childhood (SUDC) is an understudied public health issue with multiple potential risk factors, including undiagnosed cardiac and seizure disorders, for which genetic risk factors can contribute. Methods: We studied whole exome sequence data from 124 consecutively ascertained trios (decedent child and unaffected parents) to test for excessive de novo mutations in cardiac, epilepsy and other genes. Findings: Among SUDC decedents, nonsynonymous mutations were enriched in genes associated with cardiac and seizure disorders relative to non-sudden death controls (odds ratio=9.76, p=2.15x10-4). Beyond these genes there was a trend for excess loss-of-function mutations in genes that are loss-of-function intolerant (odds ratio=2.34, p=0.08). In our cohort, two genes had recurrent missense mutations, RYR2 and CACNA1C. Both RYR2 mutations are known as pathogenic (p=1.7x10-7). Both CACNA1C mutations are within a short (104 nucleotide) exon (p=1.0x10-7). We found evidence for over-transmission of loss-of-function or pathogenic variants within cardiac and seizure disorder genes (11/14 transmitted, p=0.03). Interpretation: Eleven of 124 (8.9%) decedents carried likely pathogenic or pathogenic variants associated with sudden death via a lethal cardiac or seizure disorder. Of these, 7 were de novo in origin, 1 was a transmitted parental mosaic mutation, and 3 were transmitted from heterozygous parents. Funding Statement: This study was supported by funding from the SUDC Foundation and Finding A Cure for Epilepsy and Seizures (NYU). RWT was supported by NIH grants R01 DA040484 and R01 MH71739. MJA and DJT were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Declaration of Interests: MJA is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, Myokardia, and St. Jude Medical. MJA and Mayo Clinic have an equity/royalty relationship with AliveCor, Blue Ox Health, and StemoniX. However, none of these entities are related to study. DG reports he is cofounder and holds equity in Q State – Pairnomix and Praxis Therapeutics, and equity in Apostle Inc. He receives personal fees from AstraZeneca, outside the submitted work. RT reports his participation on the Scientific Advisory boards of Howard Hughes Medical Institute, the Institute of Neuroscience (Shanghai), and the Institute of Science and Technology (Vienna). RT also reports his participation in the Actelion Scientific Advisory Board (Basel) with no compensation during 3 year span. OD reports equity interest in Empatica and receive funding from NINDS on SUDEP research. MJA, OD and PL are members of the SUDC Foundation’s scientific advisory board. LGC is President of the SUDC Foundation. MJA, OD, PL and LGC do not participate in grant funding decisions or negotiations by the SUDC Foundation to NYU Langone Health. PL, DMH, RR, XW, JP have no declarations of interests. Ethics Approval Statement: Parental consent was obtained in this NYU Institutional Review Board approved study (# S14-01061).