title: Development and Validation of Clinical Whole-Exome and Whole-Genome Sequencing for Detection of Germline Variants in Inherited Disease.
abstract: BACKGROUND
  - With the decrease in the cost of sequencing, the clinical testing paradigm has shifted from single gene to gene panel and now whole-exome and whole-genome sequencing. Clinical laboratories are rapidly implementing next-generation sequencing-based whole-exome and whole-genome sequencing. Because a large number of targets are covered by whole-exome and whole-genome sequencing, it is critical that a laboratory perform appropriate validation studies, develop a quality assurance and quality control program, and participate in proficiency testing.
  
  
  OBJECTIVE
  - To provide recommendations for whole-exome and whole-genome sequencing assay design, validation, and implementation for the detection of germline variants associated in inherited disorders.
  
  
  METHODS
  - An example of trio sequencing, filtration and annotation of variants, and phenotypic consideration to arrive at clinical diagnosis is discussed.
  
  
  CONCLUSIONS
  - It is critical that clinical laboratories planning to implement whole-exome and whole-genome sequencing design and validate the assay to specifications and ensure adequate performance prior to implementation. Test design specifications, including variant filtering and annotation, phenotypic consideration, guidance on consenting options, and reporting of incidental findings, are provided. These are important steps a laboratory must take to validate and implement whole-exome and whole-genome sequencing in a clinical setting for germline variants in inherited disorders.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
authors.forename: Avni
authors.initials: A
authors.lastname: Santani
authors.forename: Rong
authors.initials: R
authors.lastname: Mao
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferreira-Gonzalez
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.affiliation: From the Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia (Dr Hegde); the Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Dr Santani); the Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (Dr Santani); the Department of Pathology, ARUP Laboratories Institute for Clinical and Experimental Pathology, and University of Utah School of Medicine, Salt Lake City (Drs Mao and Voelkerding); the Division of Molecular Diagnostics, Department of Pathology, Virginia Commonwealth University, Richmond (Dr Ferreira-Gonzalez); and the Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (Dr Weck).
authors.forename: Karl V
authors.initials: KV
authors.lastname: Voelkerding
mesh_terms: D064790:Clinical Laboratory Services / Q000592:standards; D059472:Exome / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics*; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D018095:Germ-Line Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D033162:Incidental Findings; D017422:Sequence Analysis, DNA / Q000379:methods