What should I know about clinical exome sequencing?

Clinical Exome Sequencing is a test for identifying disease-causing DNA variants within the 1% of the genome which codes for proteins (exons) or flanks the regions which code for proteins (splice junctions).  This test is intended for use in conjunction with the clinical presentation and other markers of disease progression for the management of patients with rare genetic disorders.  Even though there are over 2,000 Mendelian diseases caused by known DNA variants, many patients who are suspected or have been clinically demonstrated to have rare genetic disorders do not receive a molecular diagnosis, often due to genetic heterogeneity and the relative inefficiency of the current sequencing technology.  It is widely accepted that about 85% of known disease-causing variants occur within the 1% of the genome containing the exons and splice junctions; thus, surveying just this portion of the genome is an efficient and powerful clinical diagnostic tool for individual patients.

By surveying virtually all protein-coding regions in the genome with this single test we not only replace the potential need for multiple costly single-gene sequencing tests but also drastically improve the odds of identifying a high-risk variant, which can then be used to guide appropriate clinical management. Utilizing an Agilent SureSelect capture kit and an Illumina HiSeq2500 next-generation sequencer, with standard operating procedures validated and implemented in the CLIA-certified UCLA Clinical Genomics Center, approximately 95% of the protein-coding sequence of all current clinically-offered disease genes are assessed by this single test.  The intent of this test is to provide a genome-wide and comprehensive genomics assessment that is cost-effective and substantially more efficient than current sequential or targeted panel testing practices.

To accomplish this, we generate over 10 billion bases of raw sequence data per patient so that, on average, every protein-coding DNA base is sampled over 100 times.  Using our informatics pipeline, we are able to find 95% of all DNA variants within the targeted region of the genome. On average, 20,000 DNA variants are detected in exons per patient. However, the vast majority of these DNA variants are benign polymorphisms.  To identify the potential disease-causing variants, we apply a series of filters to these data, which are specific for each patient including family history, any differential diagnoses, and all relevant components of the patient's condition.  This effectively searches for all genes reported in the medical literature and mutation databases which are known to cause any of the physician-provided phenotypes and include known protein-damaging variants.  These data are presented to our Genomics Data Board which includes Board Certified Pathologists, Molecular Geneticists, Molecular Cytogeneticists, Clinical Geneticists, Genetic Counselors, and Informatics Specialists where all of the data are reviewed.  In practice, about 50% of the patients have a clearly causal DNA variant identified.  If no clearly causal variant is identified, the other possible disease-causing variants are stored for potential reanalysis at a later date as new findings are published in the literature.  We may also recommend additional sequencing of other family members of those DNA variants in question in order to assist with analysis and interpretation.

How can I make an appointment to see a medical geneticist or genetic counselor?

Because this testing is complex, we recommend genetic counseling prior to testing. To locate a genetic counselor, please visit the UCLA Medical Genetics Clinic or contact us at (310) 206-6581.


  1. Clinical exome sequencing for genetic identification of rare Mendelian disorders. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF. JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604. PMID: 25326637