Expediting rare disease diagnosis: a call to bridge the gap between clinical and functional genomics
- PDF / 1,109,678 Bytes
- 7 Pages / 595.276 x 790.866 pts Page_size
- 103 Downloads / 183 Views
Molecular Medicine
Open Access
PERSPECTIVE
Expediting rare disease diagnosis: a call to bridge the gap between clinical and functional genomics Samantha N. Hartin1,2†, John C. Means1,2†, Joseph T. Alaimo1,2,3,4 and Scott T. Younger1,2,3,5*
Abstract Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8 years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease. Keywords: Rare disease diagnosis, Functional genomics, Massively parallel genomic assays, Pooled CRISPR screening Background Approximately 400 million individuals worldwide are directly affected by a rare disease (Wakap et al. 2019; Global Genes:RARE Facts 2020). Roughly 70% of rare diseases are exclusively pediatric-onset and 30% of children with a rare disease will not live to 5 years of age (Wakap et al. 2019; Global Genes:RARE Facts 2020). At present, the average time from disease onset to accurate diagnosis for a rare disease is 4.8 years (Global Genes:RARE Facts 2020; Blöß et al. 2017). Reducing the time required for disease diagnosis holds the promise of improving the quality of life for rare disease patients and in some cases may provide a window for therapeutic intervention that would otherwise be missed. Improved DNA sequencing technologies and decreases in the cost of DNA sequencing have led to the routine use of whole exome sequencing (WES) and whole *Correspondence: [email protected] † Samantha N. Hartin and John C. Means contributed equally to this work 1 Center for Pediatric Genomic Medicine, Children’s Mercy Kansas City, Kansas City, MO 64108, USA Full list of author information is available at the end of the article
genome sequencing (WGS) in a clinical setting. While the application of these technologies has greatly facilitated the identification of disease-associated genetic variants, the rate of diagnosis for rare disease remains below 50% (Soden et al. 2014; Yang et al. 2014; Lee et al. 2014). Increased accessibility of DNA sequencing has also had a pronounced impact on the field of functional genomics. High-throughput sequencing-based assays have made it possible to simultaneously profile the functional capacity of thousands of DNA sequences in a single experiment (Melnikov et al. 2012; Kheradpour et al. 2013). Despite the inherent power of these experimental approaches, their application in clinical settings have been limited. Here we propose that high-throughput functional assays capable of profiling the im
Data Loading...
