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                            Funding & Awards
 Enhancing Molecular Autopsies through High Throughout Function Assays and Family Studies of Cardiac Arrhythmogenic Variants in Sudden Unexplained Infant Deaths
Award Information
Awardee
              City of New York, Office of Chief Medical Examiner
Award #
              2015-DN-BX-K017
Funding Category
              Competitive
Location
                    New York, NY
Congressional District
              11
Status
              Closed
Funding First Awarded
              2015
Total funding (to date)
              $712,168
Original Solicitation
              NIJ FY 15 Research and Development in Forensic Science for Criminal Justice Purposes
Description of original award (Fiscal Year 2015, $712,168)
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



  
Grant-Funded Publications
        
                      Enhancing Molecular Autopsies through Function Assays and Family Studies of Cardiac Arrhythmogenic Variants in Sudden Unexplained Deaths
                  Using postmortem formalin fixed paraffin-embedded tissues for molecular testing of sudden cardiac death: A cautionary tale of utility and limitations
                  Functional Characterization of SCN10A Variants in Several Cases of Sudden Unexplained Death
                  Functional Characterization of ABCC9 Variants Identified in Sudden Unexpected Natural Death
                  Functional Reclassification of Variants of Uncertain Significance in the HCN4 Gene Identified in Sudden Unexpected Death
                  Genetic Testing in Sudden Unexpected Natural Death in the Young: New York City Office of Chief Medical Examiner's Experience and Perspective
                  Phenotypic Variations in Carriers of Predicted Protein-truncating Ggenetic Variants in MYBPC3 an Autopsy-based Case Series
                  Functional characterization of TRPM4 variants identified in sudden unexpected natural death
                  Molecular autopsy: using the discovery of a novel de novo pathogenic variant in the KCNH2 gene to inform healthcare of surviving family
                  Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function

  
Date Created: September 17, 2015
    
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