Developing genome and exome sequencing for candidate gene identification in inherited disorders: an integrated technical and bioinformatics approach.

CONTEXT Advances in sequencing technology with the commercialization of next-generation sequencing (NGS) has substantially increased the feasibility of sequencing human genomes and exomes. Next-generation sequencing has been successfully applied to the discovery of disease-causing genes in rare, inherited disorders. By necessity, the advent of NGS has fostered the concurrent development of bioinformatics approaches to expeditiously analyze the large data sets generated. Next-generation sequencing has been used for important discoveries in the research setting and is now being implemented into the clinical diagnostic arena. OBJECTIVE To review the current literature on technical and bioinformatics approaches for exome and genome sequencing and highlight examples of successful disease gene discovery in inherited disorders. To discuss the challenges for implementing NGS in the clinical research and diagnostic arenas. DATA SOURCES Literature review and authors' experience. CONCLUSIONS Next-generation sequencing approaches are powerful and require an investment in infrastructure and personnel expertise for effective use; however, the potential for improvement of patient care through faster and more accurate molecular diagnoses is high.

[1]  Hugo Y. K. Lam,et al.  Performance comparison of exome DNA sequencing technologies , 2011, Nature Biotechnology.

[2]  J. Hicks,et al.  Insight into the heterogeneity of breast cancer through next-generation sequencing. , 2011, The Journal of clinical investigation.

[3]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[4]  David P Bick,et al.  Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease , 2011, Genetics in Medicine.

[5]  E. Eichler,et al.  Combinatorial algorithms for structural variation detection in high-throughput sequenced genomes. , 2009, Genome research.

[6]  Alexander F. Wilson,et al.  Research in Genomic Medicine the Clinseq Project: Piloting Large-scale Genome Sequencing for Material Supplemental , 2009 .

[7]  Muin J Khoury,et al.  Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time , 2011, Genetics in Medicine.

[8]  R. Wilson,et al.  BreakDancer: An algorithm for high resolution mapping of genomic structural variation , 2009, Nature Methods.

[9]  Iuliana Ionita-Laza,et al.  Finding disease variants in Mendelian disorders by using sequence data: methods and applications. , 2011, American journal of human genetics.

[10]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[11]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[12]  W. Ansorge.  Next-generation DNA sequencing techniques. , 2009, New biotechnology.

[13]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[14]  P. Green,et al.  Base-calling of automated sequencer traces using phred. I. Accuracy assessment. , 1998, Genome research.

[15]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[16]  C. Furusawa,et al.  Comparison of Sequence Reads Obtained from Three Next-Generation Sequencing Platforms , 2011, PloS one.

[17]  P. Stankiewicz,et al.  Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. , 2010, The New England journal of medicine.

[18]  Warren C. Lathe,et al.  Prediction of deleterious human alleles. , 2001, Human molecular genetics.

[19]  H. Hakonarson,et al.  Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. , 2011, American journal of human genetics.

[20]  Madhuri R Hegde,et al.  Targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation , 2011, Genetics in Medicine.

[21]  P Green,et al.  Base-calling of automated sequencer traces using phred. II. Error probabilities. , 1998, Genome research.

[22]  Paul Flicek,et al.  The functional spectrum of low-frequency coding variation , 2011, Genome Biology.

[23]  Matthew W. Anderson,et al.  A multi-site study using high-resolution HLA genotyping by next generation sequencing. , 2011, Tissue antigens.

[24]  S. Levy,et al.  Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy , 2010, Nature Genetics.

[25]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[26]  Stephen C. J. Parker,et al.  Accurate and comprehensive sequencing of personal genomes. , 2011, Genome research.

[27]  Tsuyoshi Sekizuka,et al.  Genomewide Screening for Novel Genetic Variations Associated with Ciprofloxacin Resistance in Bacillus anthracis , 2010, Antimicrobial Agents and Chemotherapy.

[28]  Michael Krawczak,et al.  The human gene mutation database , 1998, Nucleic Acids Res..

[29]  M. Cronin,et al.  Whole cancer genome sequencing by next-generation methods. , 2011, American journal of clinical pathology.

[30]  Dmitry Pushkarev,et al.  Single-molecule sequencing of an individual human genome , 2009, Nature Biotechnology.

[31]  Emily H Turner,et al.  Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome , 2010, Nature Genetics.

[32]  P. Hufnagl,et al.  Sequence Capture and Next Generation Resequencing of the MHC Region Highlights Potential Transplantation Determinants in HLA Identical Haematopoietic Stem Cell Transplantation , 2011, DNA research : an international journal for rapid publication of reports on genes and genomes.

[33]  Elizabeth T. Cirulli,et al.  Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene , 2010, PLoS genetics.

[34]  S. Salzberg,et al.  Repetitive DNA and next-generation sequencing: computational challenges and solutions , 2011, Nature Reviews Genetics.

[35]  M. Ferber,et al.  Expanding DNA diagnostic panel testing: is more better? , 2011, Expert review of molecular diagnostics.

[36]  P. Shannon,et al.  Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing , 2010, Science.

[37]  James R. Knight,et al.  Genome sequencing in microfabricated high-density picolitre reactors , 2005, Nature.

[38]  D. Bentley,et al.  Whole-genome re-sequencing. , 2006, Current opinion in genetics & development.

[39]  M. Metzker.  Sequencing technologies — the next generation , 2010, Nature Reviews Genetics.

[40]  Sebastian Bauer,et al.  Identity-by-descent filtering of exome sequence data for disease–gene identification in autosomal recessive disorders , 2011, Bioinform..

[41]  Shale Dames,et al.  Next generation sequencing for clinical diagnostics-principles and application to targeted resequencing for hypertrophic cardiomyopathy: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology. , 2010, The Journal of molecular diagnostics : JMD.

[42]  Jiannis Ragoussis,et al.  Preparation of high-quality next-generation sequencing libraries from picogram quantities of target DNA. , 2012, Genome research.

[43]  Michael C. Rusch,et al.  CREST maps somatic structural variation in cancer genomes with base-pair resolution , 2011, Nature Methods.

[44]  Nada Jabado,et al.  What can exome sequencing do for you? , 2011, Journal of Medical Genetics.

[45]  M. Wilkins,et al.  Sequencing and Validation of the Genome of a Campylobacter concisus Reveals Intra-Species Diversity , 2011, PloS one.

[46]  G. Garosi,et al.  Advances in Alport syndrome diagnosis using next-generation sequencing , 2011, European Journal of Human Genetics.

[47]  B. Browning,et al.  Haplotype phasing: existing methods and new developments , 2011, Nature Reviews Genetics.

[48]  Christophe Dessimoz,et al.  Base-calling for next-generation sequencing platforms , 2011, Briefings Bioinform..

[49]  T. Hudson,et al.  Unraveling the genetics of cancer: genome sequencing and beyond. , 2011, Annual review of genomics and human genetics.

[50]  Christian Gilissen,et al.  Unlocking Mendelian disease using exome sequencing , 2011, Genome Biology.

[51]  K. Voelkerding,et al.  Next-generation sequencing: from basic research to diagnostics. , 2009, Clinical chemistry.

[52]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[53]  David R. Murdock,et al.  Whole-Genome Sequencing for Optimized Patient Management , 2011, Science Translational Medicine.

[54]  Jay Shendure,et al.  Next generation sequence analysis for mitochondrial disorders , 2009, Genome Medicine.

[55]  Gary A. Churchill,et al.  The future of model organisms in human disease research , 2011, Nature Reviews Genetics.

[56]  Yudi Pawitan,et al.  Revisiting Mendelian disorders through exome sequencing , 2011, Human Genetics.

[57]  Emily H Turner,et al.  Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes , 2009, Nature.

[58]  S. Henikoff,et al.  Predicting deleterious amino acid substitutions. , 2001, Genome research.

[59]  Serafim Batzoglou,et al.  Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++ , 2010, PLoS Comput. Biol..

[60]  Ying Liu,et al.  Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications. , 2011, Discovery medicine.

[61]  Ewan Birney,et al.  Ensembl Genome Browser , 2010 .

[62]  Philip M. Kim,et al.  Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome , 2007, Science.

[63]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[64]  A. Tretyn,et al.  Sequencing technologies and genome sequencing , 2011, Journal of Applied Genetics.

[65]  Sivakumar Gowrisankar,et al.  Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications. , 2010, The Journal of molecular diagnostics : JMD.

[66]  Ali Bashir,et al.  A geometric approach for classification and comparison of structural variants , 2009, Bioinform..

[67]  Joshua M. Korn,et al.  Mapping and sequencing of structural variation from eight human genomes , 2008, Nature.

[68]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[69]  N. Lennon,et al.  Next-generation sequencing for HLA typing of class I loci , 2011, BMC Genomics.