In the past 5 years transcriptome or RNA-sequencing (RNA-seq) has steadily emerged as a complementary assay for rare disease diagnosis and discovery. In this perspective, we summarize several recent developments and challenges in the use of RNA-seq for rare disease investigation. Using an accessible patient sample, such as blood, skin, or muscle, RNA-seq enables the assay of expressed RNA transcripts. Analysis of RNA-seq allows the identification of aberrant or outlier gene expression and alternative splicing as functional evidence to support rare disease study and diagnosis. Further, many types of variant effects can be profiled beyond coding variants, as the consequences of noncoding variants that impact gene expression and splicing can be directly observed. This is particularly apparent for structural variants that disproportionately underlie outlier gene expression and for splicing variants in which RNA-seq can both measure aberrant canonical splicing and detect deep intronic effects. However, a major potential limitation of RNA-seq in rare disease investigation is the developmental and cell type specificity of gene expression as a pathogenic variant's effect may be limited to a specific spatiotemporal context and access to a patient's tissue sample from the relevant tissue and timing of disease expression may not be possible. We speculate that as advances in computational methods and emerging experimental techniques overcome both developmental and cell type specificity, there will be broadening use of RNA sequencing and multiomics in rare disease diagnosis and delivery of precision health. <<<

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality. <<<