A Clinician’s perspective on clinical exome sequencing
- 946 Downloads
Clinical exome sequencing has clearly improved our ability as clinicians to identify the cause of a wide variety of disorders. Prior to exome sequencing, a majority of patients with apparent syndromes never received a specific molecular genetic diagnosis despite extensive diagnostic odysseys. Even for those receiving an answer to the question of what caused their disorder, the diagnostic odyssey often spanned years to decades. Determining the particular genetic cause in an individual patient can be challenging due to inherent phenotypic and genetic heterogeneity of disease, technical limitations of testing or both. Blended phenotypes, due to multiple monogenic disorders in the same patient, are true dilemmas for traditional genetic evaluations, but are increasingly being diagnosed through clinical exome sequencing. New sequencing technologies have increased the proportion of patients receiving molecular diagnoses, while significantly shortening the time scale, providing multiple benefits for the health-care team, patient and family.
KeywordsWhole Genome Sequencing Exome Sequencing Genetic Diagnosis Pathogenic Variant Gene Panel
DTM receives partial funding through grant NHGRI U41 HG006834 “ClinGen: a Clinical Genomics Database,” and is a part-time clinical consultant for Claritas Genomics through a non-equity professional services agreement. AHOL is supported by the Pfizer/ACMGF Clinical Genetics Fellowship for Translational Genomic Scholars.
- Amor D, Rose C, White S, et al (2016) POSSUMweb. http://www.possum.net.au. Accessed 25 Jan 2016
- Farwell KD, Shahmirzadi L, El-Khechen D et al (2015) Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med Off J Am Coll Med Genet 17:578–586. doi: 10.1038/gim.2014.154 Google Scholar
- Fryns J-P, de Ravel TJL (2002) London Dysmorphology Database, London Neurogenetics Database and Dysmorphology Photo Library on CD-ROM [Version 3] 2001R. M. Winter, M. Baraitser, Oxford University Press, ISBN 019851-780, pound sterling 1595. Hum Genet 111:113. doi: 10.1007/s00439-002-0759-6 CrossRefPubMedGoogle Scholar
- Genetic and Rare Diseases (GARD) Information Center: Natl. Inst. Health Off. Rare Dis. https://rarediseases.info.nih.gov/. Accessed 30 Dec 2015
- Gripp KW, Slavotinek AM, Hall JG, Allanson JE (2013) Handbook of physical measurements, 3rd edn. Oxford University Press, Oxford, UKGoogle Scholar
- Lek M, Karczewski K, Minikel E et al (2015) Analysis of protein-coding genetic variation in 60,706 humans. bioRxiv, Art id 030338Google Scholar
- Miller DT, Adam MP, Aradhya S et al (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764. doi: 10.1016/j.ajhg.2010.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
- Pagon RA, Adam MP, Ardinger HH et al. (eds) (1993–2016). GeneReviews® [Internet]. University of Washington, Seattle. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1116/
- Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med Off J Am Coll Med Genet 17:405–424. doi: 10.1038/gim.2015.30 Google Scholar
- Soden SE, Saunders CJ, Willig LK et al (2014) Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 6:265ra168. doi: 10.1126/scitranslmed.3010076
- Stenson PD, Mort M, Ball EV et al (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9. doi: 10.1007/s00439-013-1358-4 CrossRefPubMedPubMedCentralGoogle Scholar