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" (<2 months or >4 months) SIDS cases will harbor an increased burden of rare variants in metabolic, immunologic, or channelopathic pathway(s).
Over 2000 seemingly healthy infants die inexplicably each year, a sudden, unexpected, and unexplained death labeled as sudden infant death syndrome (SIDS). The purpose of this study is to discover fundamental pathogenic causes/substrates for the infant vulnerability that underlies SIDS with a focus on genes that regulate the heart's electrical system, central and autonomic nervous system, immune system, metabolism, and nicotinergic/serotonergic response systems.
|Hennessey, Jessica A; Boczek, Nicole J; Jiang, Yong-Hui et al. (2014) A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis. PLoS One 9:e106982|
|Wang, Wei; Landstrom, Andrew P; Wang, Qiongling et al. (2014) Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice. Am J Physiol Heart Circ Physiol 307:H1317-26|
|Kapplinger, Jamie D; Landstrom, Andrew P; Bos, J Martijn et al. (2014) Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. J Cardiovasc Transl Res 7:347-61|
|Bos, J Martijn; Will, Melissa L; Gersh, Bernard J et al. (2014) Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. Mayo Clin Proc 89:727-37|
|Saul, J Philip; Schwartz, Peter J; Ackerman, Michael J et al. (2014) Rationale and objectives for ECG screening in infancy. Heart Rhythm 11:2316-21|
|Giudicessi, John R; Ackerman, Michael J (2013) Genotype- and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol 38:417-55|
|Crotti, Lia; Tester, David J; White, Wendy M et al. (2013) Long QT syndrome-associated mutations in intrauterine fetal death. JAMA 309:1473-82|
|Giudicessi, John R; Ackerman, Michael J (2013) Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise. Curr Opin Cardiol 28:63-71|
|Reynolds, Julia O; Chiang, David Y; Wang, Wei et al. (2013) Junctophilin-2 is necessary for T-tubule maturation during mouse heart development. Cardiovasc Res 100:44-53|
|Tester, David J; Ackerman, Michael J (2012) The molecular autopsy: should the evaluation continue after the funeral? Pediatr Cardiol 33:461-70|
Showing the most recent 10 out of 93 publications