Exome and Whole-Genome Sequencing as Clinical Tests: A Transformative Practice in Molecular Diagnostics

Abstract

In the last few years, next-generation sequencing (NGS)5 has revolutionized the approaches by which we interrogate the genetic causes of rare single-gene disorders (1). More recently, NGS has been rapidly moving into the clinical diagnostics arena and transforming the practice of molecular diagnostics testing. Many NGS-based tests for multigene panels are available in clinical laboratories. Now, proof-of-principle studies are demonstrating the feasibility of using exome sequencing for clinical testing (2–4). Dixon-Salazar et al. used exome sequencing to interrogate a cohort of 118 probands with recessive neurodevelopmental disorders and identified disease-causing mutations in 19% of the probands. Importantly, exome sequencing uncovered mutations in 10 probands (8% of the cohort) that altered the initial clinical diagnosis and led in some cases to a change in patient management (2). Calvo et al. tested 42 infants with mitochondrial diseases with the “MitoExome” (mitochondrial DNA plus exons of approximately 1000 nuclear genes) and confirmed that 10 patients (24% of the cohort) had pathogenic mutations. In addition, these investigators identified 2 novel disease-causing genes (3). Need et al. used exome sequencing in family trios to investigate patients with a broad range of phenotypic presentations and reported a 33% diagnostic yield: 4 of 12 patients with apparently causal mutations and 2 additional potentially novel disease-causing genes (4). Although the number of patients tested thus far by whole-exome sequencing (WES) or whole-genome sequencing (WGS) is still small, the data reported in these recent studies have defined the minimal diagnostic yields of such NGS-based clinical tests at their early stage of implementation, thus demonstrating the practicality of NGS-based tests. We anticipate that the clinical utility of NGS-based tests will improve further in the next few years and that more patients will benefit from improved diagnostic accuracy and more-appropriate treatment. Conventional molecular diagnostics tests evaluate a defined …