DESCRIPTION (provided by applicant): With over 2000 deaths each year in the United States, sudden infant death syndrome (SIDS) remains a leading cause of death in infants under 1 year of age. In order to reach the ultimate goal of the NICHD to eradicate this emotionally devastating syndrome, it is vital to understand the underlying etiologies and pathogenesis of this multifactorial syndrome. However, the fundamental causes of SIDS remain poorly understood. Underlying genetic susceptibility for sudden death, involving genetic determinants of the central nervous system and serotonergic signaling, immune dysfunction, metabolism/energy pathway, nicotine response, and cardiac repolarization, may represent pathogenic substrates for infant vulnerability in accordance with the SIDS triple risk hypothesis for a significant number of SIDS cases. The genetics of SIDS is most likely multigenic and complex yet there has been no studies performed to elucidate the global genetic load. Through the use of monumental technological advances in genomic research, including array comparative genomic hybridization (aCGH) and next-generation whole- exome DNA sequencing (WES), it is our broad objective to perform the first whole genome interrogation of one of the world's largest assembled, multi-ethnic SIDS cohorts (n=625; 303 Caucasian, 203 African American, 96 Hispanic, 14 Asian, and 9 mixed race) in order 1) to explore the novel concept of increased radical de novo mutation (DNM) rate among SIDS victims as a paradigm shift in explaining the paradoxical sustained world-wide prevalence of SIDS by performing aCGH and WES on SIDS case-parent trios, 2) to establish the spectrum, prevalence, and biological pathway involvement of copy number variations (CNV) as an underlying genetic susceptibility for SIDS, and 3) to establish a Genetic Blueprint of Infant Vulnerability across multiple disciplines using WES and pathway/network analysis of genes identified with rare non-synonymous genetic variants, to ascertain whether specific SIDS-associated molecular biological pathways (i.e. serotonergic pathways, immune response deficiencies, cardiac repolarization abnormalities, etc.) or signaling networks are predominantly effected. The proposed experiments will test our three-fold hypothesis that 1) rare DNMs with clear functional significance will be identified in novel SIDS-susceptibility genes and pathways and the underlying DNM rate, defined as the ratio of non-synonymous (NS) to synonymous DNMs, and the ratio of nonsense to missense DNMs in SIDS will exceed the ratio previously established in healthy living subjects, 2) a significant number of SIDS cases are due to rare CNVs typified as deletions and/or duplications of DNA segments of e 1kilobase in length that alter either imbalances of dosage or disruption of neurodevelopmental, CNS signaling, metabolic, immunologic, and/or cardiac channelopathic genes, and 3) rare genetic variants in SIDS will be over-dispersed to genes comprising SIDS-susceptibility pathways with classical (2 to 4 months of age) SIDS cases harboring an increase burden of rare variants in a neurodevelopmental pathways while non-classical ( 4 months) SIDS cases will harbor an increased burden of rare variants in metabolic, immunologic, or channelopathic pathway(s).
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