Journal ArticleDOI
A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases
Kornelia Neveling,Ilse Feenstra,Christian Gilissen,Lies H. Hoefsloot,Erik-Jan Kamsteeg,Arjen R. Mensenkamp,Richard J. Rodenburg,Helger G. Yntema,Liesbeth Spruijt,Sascha Vermeer,Tuula Rinne,Koen L.I. van Gassen,Danielle Bodmer,Dorien Lugtenberg,Rick de Reuver,Wendy Buijsman,Ronny 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 Marcelis,Jan A.M. Smeitink,Saskia B. Wortmann,Wendy A. G. van Zelst-Stams,Joris A. Veltman,Han G. Brunner,Hans Scheffer,Marcel R. Nelen +31 more
TLDR
It is found that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders, and for microsatellite‐stable colorectal cancer, this was low under both strategies.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.read more
Citations
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Journal ArticleDOI
Guidelines for diagnostic next-generation sequencing.
Gert Matthijs,Erika Souche,Marielle Alders,Anniek Corveleyn,Sebastian Eck,Ilse Feenstra,Valerie Race,Erik A. Sistermans,Marc Sturm,Marjan M. Weiss,Helger G. Yntema,Egbert Bakker,Hans Scheffer,Peter Bauer +13 more
TL;DR: These guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe.
Journal ArticleDOI
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
Stefan H. Lelieveld,Margot R.F. Reijnders,Rolph Pfundt,Helger G. Yntema,Erik-Jan Kamsteeg,Petra de Vries,Bert B.A. de Vries,Marjolein H. Willemsen,Tjitske Kleefstra,Katharina Löhner,Maaike Vreeburg,Servi J. C. Stevens,Ineke van der Burgt,Ernie M.H.F. Bongers,Alexander P.A. Stegmann,Patrick Rump,Tuula Rinne,Marcel R. Nelen,Joris A. Veltman,Joris A. Veltman,Lisenka E.L.M. Vissers,Han G Brunner,Han G Brunner,Christian Gilissen +23 more
TL;DR: Ten new candidate genes for intellectual disability are identified and it is shown that these genes are intolerant to nonsynonymous variation and that mutations inThese genes are associated with specific clinical ID phenotypes.
Journal ArticleDOI
Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature.
TL;DR: The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited and studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.
Journal ArticleDOI
A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders
Zornitza Stark,Tiong Yang Tan,Belinda Chong,Gemma R Brett,Patrick Yap,Maie Walsh,Alison Yeung,Heidi Peters,Heidi Peters,Dylan A. Mordaunt,Dylan A. Mordaunt,Shannon Cowie,David J. Amor,Ravi Savarirayan,George McGillivray,Lilian Downie,Paul G Ekert,Christiane Theda,Christiane Theda,Paul A. James,Joy Yaplito-Lee,Monique M. Ryan,Monique M. Ryan,Richard J. Leventer,Richard J. Leventer,Emma Creed,Ivan Macciocca,Katrina M. Bell,Alicia Oshlack,Simon Sadedin,Peter Georgeson,Charlotte Anderson,Natalie P. Thorne,Clara Gaff,Susan M. White +34 more
TL;DR: Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.
Journal ArticleDOI
Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.
Sara L. Sawyer,Taila Hartley,David A. Dyment,Chandree L. Beaulieu,Jeremy Schwartzentruber,Amanda C. Smith,H M Bedford,Geneviève Bernard,Francois P. Bernier,Bernard Brais,Dennis E. Bulman,J. Warman Chardon,David Chitayat,Johnny Deladoëy,Bridget A. Fernandez,Patrick Frosk,Michael T. Geraghty,Brenda Gerull,William T. Gibson,Robert M. Gow,Gail E. Graham,Jane Green,Elise Héon,Gabriella Horvath,A.M. Innes,Nada Jabado,Raymond H. Kim,Robert K. Koenekoop,Aneal Khan,Ordan J. Lehmann,Roberto Mendoza-Londono,Jacques L. Michaud,Sarah M. Nikkel,L S Penney,Constantin Polychronakos,Julie Richer,Guy A. Rouleau,Mark E. Samuels,Victoria Mok Siu,Oksana Suchowersky,Mark A. Tarnopolsky,Grace Yoon,Farah R. Zahir,Jacek Majewski,Kym M. Boycott +44 more
TL;DR: The analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases.
References
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Journal ArticleDOI
A method and server for predicting damaging missense mutations.
Ivan Adzhubei,Steffen Schmidt,Leonid Peshkin,Vasily Ramensky,Anna Gerasimova,Peer Bork,Alexey S. Kondrashov,Shamil R. Sunyaev +7 more
TL;DR: A new method and the corresponding software tool, PolyPhen-2, which is different from the early tool polyPhen1 in the set of predictive features, alignment pipeline, and the method of classification is presented and performance, as presented by its receiver operating characteristic curves, was consistently superior.
Journal ArticleDOI
SIFT: predicting amino acid changes that affect protein function
Pauline C. Ng,Steven Henikoff +1 more
TL;DR: SIFT is a program that predicts whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study and can distinguish between functionally neutral and deleterious amino acid changes in mutagenesis studies and on human polymorphisms.
Journal ArticleDOI
Detection of nonneutral substitution rates on mammalian phylogenies
TL;DR: By applying phyloP to mammalian multiple alignments from the ENCODE project, it shed light on patterns of conservation/acceleration in known and predicted functional elements, approximate fractions of sites subject to constraint, and differences in clade-specific selection in the primate and glires clades.
Journal ArticleDOI
Exome sequencing as a tool for Mendelian disease gene discovery
Michael J. Bamshad,Sarah B. Ng,Abigail W. Bigham,Abigail W. Bigham,Holly K. Tabor,Holly K. Tabor,Mary J. Emond,Deborah A. Nickerson,Jay Shendure +8 more
TL;DR: Experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders and set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.
Journal ArticleDOI
Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome
Sarah B. Ng,Abigail W. Bigham,Kati J. Buckingham,Mark C. Hannibal,Mark C. Hannibal,Margaret J. McMillin,Heidi I. S. Gildersleeve,Anita E. Beck,Anita E. Beck,Holly K. Tabor,Holly K. Tabor,Gregory M. Cooper,Heather C Mefford,Choli Lee,Emily H. Turner,Joshua D. Smith,Mark J. Rieder,Koh-ichiro Yoshiura,Naomichi Matsumoto,Tohru Ohta,Norio Niikawa,Deborah A. Nickerson,Michael J. Bamshad,Michael J. Bamshad,Jay Shendure +24 more
TL;DR: The results strongly suggest that mutations in MLL2, which encodes a Trithorax-group histone methyltransferase, are a major cause of Kabuki syndrome.
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