• Kornelia Neveling, Ilse Feenstra, Christian Gilissen, Lies H Hoefsloot, Erik-Jan Kamsteeg, Arjen R Mensenkamp, Richard J T Rodenburg, Helger G Yntema, Liesbeth Spruijt, Sascha Vermeer, Tuula Rinne, Koen L van Gassen, Danielle Bodmer, Dorien Lugtenberg, Rick de Reuver, Wendy Buijsman, Ronny C Derks, Nienke Wieskamp, Bert van den Heuvel, Marjolijn J L Ligtenberg, Hannie Kremer, David A Koolen, Bart P C van de Warrenburg, Frans P M Cremers, Carlo L M Marcelis, Jan A M Smeitink, Saskia B Wortmann, Wendy A G van Zelst-Stams, Joris A Veltman, Han G Brunner, Hans Scheffer, and Marcel R Nelen.
• Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud university medical centre, Nijmegen, The Netherlands.
• Hum. Mutat. 2013 Dec 1;34(12):1721-6.

AbstractThe 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 that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes. 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 five 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.© 2013 WILEY PERIODICALS, INC.

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