Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes

Background As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which can cause heart failure and sudden death. We sought to compare the frequency and distribution of incidentally identified variants in DCM‐associated genes between a clinical referral cohort with those in control and known case cohorts to determine the likelihood of pathogenicity among those undergoing genetic testing for non‐DCM indications. Methods and Results A total of 39 rare, non‐TTN DCM‐associated genes were identified and evaluated from a clinical ES testing referral cohort (n=14 005, Baylor Genetic Laboratories) and compared with a DCM case cohort (n=9442) as well as a control cohort of population variants (n=141 456) derived from the gnomAD database. Variant frequencies in each cohort were compared. Signal‐to‐noise ratios were calculated comparing the DCM and ES cohort with the gnomAD cohort. The likely pathogenic/pathogenic variant yield in the DCM cohort (8.2%) was significantly higher than in the ES cohort (1.9%). Based on signal‐to‐noise and correlation analysis, incidental variants found in FLNC, RBM20, MYH6, DSP, ABCC9, JPH2, and NEXN had the greatest chance of being DCM‐associated. Conclusions The distribution of pathogenic variants between the ES cohort and the DCM case cohort was gene specific, and variants found in the ES cohort were similar to variants found in the control cohort. Incidentally identified variants in specific genes are more associated with DCM than others

Risk Factors for Sudden Infant Death in North Carolina

Background: Sudden infant death syndrome (SIDS) is the sudden, unexplained death of infants <1 year old. SIDS remains a leading cause of death in US infants. We aim to identify associations between SIDS and race/ethnicity, birth weight/gestational age, and socioeconomic/environmental factors in North Carolina (NC) to help identify infants at risk for SIDS. Methods and Results: In this IRB-approved study, infant mortality 2007–2016 and death certificate-linked natality 2007–2014 were obtained from the NC Department of Health and Human Services. General, NC natality statistics 2007–2016 were obtained from CDC Wonder. Association between SIDS/total infant death and covariates (below) were calculated. Total infant mortality decreased 2007–2016 by an average of 14 deaths/100,000 live births per year, while SIDS incidence remained constant. Risk ratios of SIDS/total infant deaths, standardized to Non-Hispanic White, were 1.76/2.41 for Non-Hispanic Black and 0.49/0.97 for Hispanic infants. Increased SIDS risk was significantly and independently associated with male infant sex, Non-Hispanic Black maternal race/ethnicity, young maternal age, low prenatal care, gestational age <39 weeks, birthweight <2500 g, low maternal education, and maternal tobacco use (p < 0.01). Maternal previous children now deceased also trended toward association with increased SIDS risk. Conclusions: A thorough SIDS risk assessment should include maternal, socioeconomic, and environmental risk factors as these are associated with SIDS in our population