title: A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases.
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 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.
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud university medical centre, Nijmegen, The Netherlands.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Ilse
authors.initials: I
authors.lastname: Feenstra
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Tuula
authors.initials: T
authors.lastname: Rinne
authors.forename: Koen L
authors.initials: KL
authors.lastname: van Gassen
authors.forename: Danielle
authors.initials: D
authors.lastname: Bodmer
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.forename: Rick
authors.initials: R
authors.lastname: de Reuver
authors.forename: Wendy
authors.initials: W
authors.lastname: Buijsman
authors.forename: Ronny C
authors.initials: RC
authors.lastname: Derks
authors.forename: Nienke
authors.initials: N
authors.lastname: Wieskamp
authors.forename: Bert
authors.initials: B
authors.lastname: van den Heuvel
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: David A
authors.initials: DA
authors.lastname: Koolen
authors.forename: Bart P C
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Saskia B
authors.initials: SB
authors.lastname: Wortmann
authors.forename: Wendy A G
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Marcel R
authors.initials: MR
authors.lastname: Nelen
mesh_terms: D059472:Exome; D005817:Genetic Counseling; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics*; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods / Q000592:standards; D006801:Humans; D017422:Sequence Analysis, DNA / Q000379:methods / Q000592:standards
keywords: NGS; diagnostic yield; exome sequencing; genome diagnostics; heterogeneous diseases