A post-hoc comparison of the utility of Sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases.

Source

Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.

Abstract

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far, it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors which include gene-specific phenotype traits, and the relative frequency of involvement of specific genes. In order to gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger based sequencing (in 2011), and exome sequencing followed by targeted bioinformatics analysis (in 2012) for 5 different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite-stable colorectal cancer this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.