Enhancing Molecular Autopsies through High Throughout Function Assays and Family Studies of Cardiac Arrhythmogenic Variants in Sudden Unexplained Infant Deaths

As submitted by the proposer: Molecular autopsies have an increasingly important role in modern forensic practice, particularly in sudden unexplained infant deaths (commonly known as SIDS). Our NIJ FY2011 Basic Research Grant project (2011-DN-BX-K535) results showed that in a large infant cohort, all of whom had comprehensive forensic investigations and complete autopsies at the New York City Office of Chief Medical Examiner (NYC OCME) and whose deaths remained still unexplained, over 30% of infants carried non-synonymous variants in cardiac arrhythmogenic genes. More than half of those variants are novel and absent from large population-based sequencing databases. These novel variants are classified as “variants of uncertain significance”. The proposed studies aim to determine the significance of these putative cardiac arrhythmogenic variants identified in SIDS and will 1) utilize high-throughput methods to characterize the effect of the genetic variants on cardiac ion channel functions and 2) utilize clinical tools to explore the inheritance of the genetic variants (i.e. fatal de novo variants, which are present only in the deceased, or pathogenic variants, which co-segregate with the clinical phenotype of biologically related family members). The overall goal of this proposal is to enhance molecular autopsies by evaluating a large number (>100) of genetic variants of “uncertain significance” through high-throughput functional assays and family studies. This is a joint application by Dr. Yingying Tang (Director of the Molecular Genetics Laboratory of NYC OCME, CAP-accredited) and Dr. William Coetzee (Professor of Pediatrics, NYU School of Medicine), who propose to establish an innovative and systematic approach to determine how the variations of ion channel genes participate in sudden infant death. We have already established a working relationship by studying SCN5A variants identified in an African-American/Hispanic girl who died suddenly in her sleep at the age of 5 weeks. Our preliminary data demonstrated severe Na+ channel defects, which may be the molecular basis for a fatal cardiac arrhythmia event in the decedent. The proposed studies will improve our understanding of the underlying causes of sudden infant deaths, serve to develop efficient approaches for better characterization of large numbers of genetic variants, and enhance the postmortem molecular diagnostic capabilities available to medical examiners, thereby, improving their ability to determine causes of death in cases which would otherwise remain “undetermined”. More importantly, our family studies will identify close family members (parents and siblings) who are potentially at risk of sudden death and who will be referred to clinical genetic centers for possible treatment. This project contains a research and/or development component, as defined in applicable law. ca/ncf