Identification of a Deletion in the LRP1b Gene associated with Megalencephaly in the Sudden Infant Death Syndrome. D. S. Paterson1, H. C. Kinney1, K. Schmitz Abe2, F. Rahimov2, F. L. Trachtenberg3, E. A. Haas4, H. F. Krous4, K. Markianos2 1) Pathology, Boston Childrens Hospital, Boston, MA; 2) Program in Genomics , Department of Pediatrics Boston Childrens Hospital, Boston, MA; 3) New England Research Institutes, Watertown, MA; 4) Rady Childrens Hospital San Diego and University of California, San Diego School of Medicine, La Jolla, CA.

   The sudden infant death syndrome (SIDS) is defined as the sudden death of an infant less than 12 months of age that is associated with a sleep period and remains unexplained after a complete autopsy and death scene investigation. It is the leading cause of postneonatal death in the United States with an overall incidence of 0.57/1,000 live births. The cause of SIDS remains unknown, but it is thought to have complex etiology involving multiple environmental and genetic risk factors. To date however, genetic studies in SIDS have failed to identify any variant that is necessary or sufficient for a SIDS death to occur. In other sporadic diseases with complex etiology, including autism, schizophrenia and Crohns disease, high penetrance cytogenetic abnormalities such as copy number variations (CNVs) play a role in disease pathogenesis. In this study, we performed genome wide analysis of SIDS cases in the San Diego SIDS Dataset in order to identify CNVs that potentially cause or contribute to the pathogenesis of SIDS. Using a comparative genomic hybridization array with DNA from 50 SIDS cases we identified a total of 384 CNVs, including a novel 100kb deletion in chromosome 2q22.1affecting the low density lipoprotein receptor-related protein 1b (LRP1b) gene. Using qPCR we confirmed the deletion in 2/50 original SIDS cases and in an additional 6/100 SIDS cases from the San Diego SIDS Dataset. The deletion was absent in 144 ethnicity and sex matched controls from Coriell Institute Human Variation Panels and in 1,200 healthy controls and ~8000 cases collected for other phenotypes. Moreover, the affected cases exhibited "somatic overgrowth", i.e., increased body metrics for age including megalencephaly, which has previously been reported, but was of unknown etiology, in SIDS. Thus, we report the identification of a novel deletion that affects the protein coding region of the LRP1b gene and that is present in ~ 5% (8/150) of SIDS cases but that has not been identified in over 9,000 non-SIDS samples. These observations suggest that gene variants altering LRP1b function play an important role in the pathogenesis of at least a subset of SIDS cases and are partially responsible for megalencephaly associated with the disease. .

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