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Clinical Exome Sequencing

Indicated for patients with undiagnosed genetic disorders

  • CES is a test that examines the portion of the genome that encodes for proteins (exons) and their flanking splice junctions.
  • CES aims to identify disease-causing variants within the exons.
  • CES interprets the identified variants within the context of the clinical presentation in order to reach a diagnosis for patients with challenging undiagnosed genetic disorders.
  • The UAGC-CS sequences full trio or proband-only exomes encompassing over 50MB of around 21,000 human genes.
  • Patients are sequenced to a depth greater than 50X coverage on a Illumina HiSeq 2500 and all data is aligned and mapped back to the human reference genome.
  • The UAGC-CS clinical report includes all validated de novo variants as well as alternate alleles found in the patient sample prioritized by known or potential pathogenicity and relation to the clinical phenotype.
  • Incidental findings are also reported if patient is consented to receive such findings.
  • Genetic counseling before and after testing is required.

clinical utility

The clinical utility of exome sequencing has been well established and evidence for the utility of exome sequencing in reaching a diagnosis for different entities of genetic disorders is growing. In a series of 250 patients without prior diagnosis, exome sequencing achieved an overall molecular diagnostic rate of 25% [1] that was higher than several other comparable genetic tests, including chromosome analysis (5-10%) [2], and chromosomal microarray analysis (15-20%). More intriguing was the fact that a small percentage of patients (4/250 (1.6%)) were diagnosed with two different mendelian disorders [1]. In a later study that included 2000 patients with different types of genetic disorders, including neurological disorder, neurological plus other organ systems, the specific neurological group included more defined neurological signs and symptoms (eg, ataxia, movement disorder, spastic paraplegia) and the non-neurological group had findings from organ systems other than neurological, a diagnostic yield of 27.2%, 24.6%, 36.1%, and 20.1% was achieved for these groups, respectively [4]. 58%of the diagnostic mutations reported in that study [4] were not previously reported. Moreover, 4.6% of patients who received molecular diagnosis had a blend of phenotypes resulting from 2 single gene defects. Another 4.6% of patients had medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management [4]. Another study examined the diagnostic yield of exome sequencing in patients with intellectual disability with IQ below 50 and achieved a diagnostic yield of 16%, mostly involving de novo mutations [5]. These findings clearly demonstrate the clinical utility of exome sequencing for a spectrum of genetic disorders.

1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders.N Engl J Med. 2013;369(16): 1502-1511.

2. Shaffer LG; American College of Medical Genetics Professional Practice and Guidelines Committee. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Genet Med. 2005;7(9):650-654.

3. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764.

4. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M, Patel A, Boerwinkle E, Beaudet AL, Lupski JR, Plon SE, Gibbs RA, Eng CM. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014 Nov 12;312(18):1870-9.

5. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9.

Criteria for Patient Testing

Each patient requisition is reviewed by a Clinical Coordinator for completeness and specimen requirements. Specific patient eligibility includes an assessment of (but is not limited to) the following criteria:

The patient’s disorder is likely to be a genetic condition

Other genetic tests have been performed or considered, if applicable

Medical history, genetic and non-genetic test results may be available for review

Appropriate relatives are available for testing, when required for result interpretation or confirmation

Patient and/or family members have undergone genetic counseling before testing and consent to testing

NOTE: This test is offered on postnatal samples only.

Specimen Requirements

Clinical Exome Sequencing
Container: Whole blood collected in a lavender top tube (K2EDTA or K3EDTA).
Volume: Adult/Child 3-7 mL; Infant 1-2 mL

Alternatively, UAGC-CS will accept buccal swabs for CES testing. Samples should be collected in duplicate, 2 buccal brushes, each preserved in Lysis Buffer (preferably a 2 mL O-ring tube).

The UAGC – CS will also accept genomic DNA for Clinical Exome Sequencing, however, DNA specimens are only accepted if the nucleic acid isolation occurred in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or the CMS.

Acceptable specimen: High molecular weight genomic DNA extracted from EDTA whole blood (lavender top tube) and treated with RNase. Minimum 10ug at 100ng/uL, preferably accompanied with 1-2% agarose gel run image and 260/280 ratio. Genomic DNA is the preferred specimen for international requests. Other tissues are not acceptable.

Turnaround Time

8−12 weeks – Times begin from receipt of the tissue sample(s) by UAGC-CS and are based on business hours of the laboratory: Monday through Friday, 9am-5pm Arizona Time. Note: Family Trio testing will begin when all samples have been received by the laboratory.

Additional Details

Information about Clinical Exome Sequencing for patients and consent form can be downloaded HERE.