Clinical utility of targeted RNAseq in neuromuscular and immune disorders

A specific genetic diagnosis leads to lower health care costs and improvement in clinical outcomes for rare congenital diseases. Despite significant advancements in sequencing technology and bioinformatic analysis, only about 35% of patients suspected of having a rare congenital disease receive a genetic diagnosis. Some of the main challenges facing WES and WGS are the interpretation of variants of uncertain significance (VUS) and accurately identifying and predicting the effect of potential splice variants. Recent research indicates RNA-seq can improve diagnostic yield for these disorders, but lack of standards for efficient analysis of RNA-seq data is a significant impediment to clinical implementation of functional assays for diagnosing rare disease. Through analysis of cohorts with neuromuscular disorders, primary immunodeficiencies, and inflammatory bowel disease, I show the clinical utility of RNA-seq and argue that my method of multi-faceted analysis in targeted RNA-seq outperforms whole transcriptome sequencing and any single tool developed for the identification of aberrant splicing.Ph.D

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach

Patterns of Care in Michigan Emergency Departments as Insurance Coverage Expands

Using the Michigan Syndromic Surveillance System changes in emergency department (ED) volume are being monitored as health insurance coverage expands through the Healthy Michigan Plan (HMP), which provides healthcare coverage to low-income adults. Seasonally adjusted monthly ED visits prior to and after the HMP implementation on April 1, 2014 are being compared. Preliminary data show increasing trends in ED utilization among populations with previously low levels of health insurance coverage. Increased health insurance coverage may expand healthcare service options beyond EDs. Alternatively, the demand for primary care services may exceed the level of access leading to increased ED utilization for primary care