Columbia Diagnostic Exome (CDEX)

Test Information

Exome Sequencing (ES) has proven to be an important tool in the implementation of individualized medicine. The interrogation of genetic variation in about 20,000 genes simultaneously is a powerful and effective diagnostic method for heterogeneous patient populations with diseases that are suspected to be genetic in origin. The diagnostic yield from ES ranges from 20 to over 50% depending on the clinical presentation and phenotype of the proband. Trio analysis consisting of the proband and both biological parents is preferred to singleton (proband only) or duo (proband and one parent) analyses. Studies comparing diagnostic yield of singleton analysis against trio analysis have generally found that trio exome sequencing provides an incremental gain of 10–15%. Trio analysis allows for the immediate identification of de novo variants, determination of phase for biallelic variants, and confirmation of carrier status in both parents when a homozygous or a compound heterozygous variant is detected.

Variant Information

We report variants in the following categories:

  • Variants in known disease genes thought to be causative of phenotype for which test is ordered: The patient may have one or more genetic variant(s) that are known to cause a specific genetic condition in other individuals with similar symptoms. Pathogenic and likely pathogenic variants considered to be causative of the patient’s symptoms would be reported under this category. Variants of uncertain clinical significance may be reported if there is evidence strongly suggesting these are related to the patient’s condition. Single variants in genes associated with autosomal recessive conditions may be reported only for clinically relevant genes.
  • Variants causing Treatable/ Preventable Conditions (diseases which are clinically actionable): We follow the guidelines of the American College of Medical Genetics and Genomics for reporting of secondary findings in clinical exome and genome sequencing. Please consult the latest version of these guidelines for an up-to-date list of genes and conditions reported in this category. Individuals have the option of opting out from receiving these results.
  • Incidental findings: ES may identify clinically significant variants in other genes that may impact clinical management. These genes are not part of the ACMG secondary findings gene list; and may be unrelated to the primary reason for testing. These types of variants may be reported at the discretion of the laboratory and the patient’s clinical team.
  • Variants in genes with a limited level of evidence for disease association (also referred to as candidate genes, genes of uncertain significance, or genes with limited evidence): Such variants will only be reported for postnatal exomes.
  • Risk alleles: these are variants that have been associated with a slight or moderate increased risk for common diseases, such as blood clotting disorders. These types of variants may be reported at the discretion of the laboratory if they are considered to be related to phenotype. Such variants will only be reported for postnatal exomes.

Options

Patients have the option of opting out from receiving secondary findings. Please note that full secondary finding analysis will only be performed for the patient. Only secondary findings identified in the patient will be reported in family members who submit samples. Family members will not have an independent analysis for secondary findings.

Test Methods and Performance

Columbia Diagnostic EXome sequencing (CDEX) test interrogates genetic variations in the coding regions and the splice junctions of the human genome. For the CDEX test, the exome is sequenced to achieve an average minimum depth of 100X. On average, >98% of target region is covered at ≥10X. Percentage of unique mapped reads is >70% and specificity on target is >50%. CDEX can perform both singleton and trio analysis (when parental samples are submitted) and the joint analysis is performed to maximize sensitivity and specificity. Proband (only) or Trio analysis (proband with parents) is performed via the in-house Analysis Tool for Annotated Variants (ATAV) for variant filtering and prioritization.

Limitations and Risks

Limitations: ES is not able to detect mutations in the 99% of the DNA that is not part of the exome, including parts of the DNA that help regulate gene function. Coverage might vary by gene.

Variation calling performance may vary by DNA sequence context. ES is not currently validated to detect large‐scale alterations (such as microdeletions or microduplications), chromosome rearrangements (such as translocations), genetic disorders that are caused by expansion of repetitive regions of the genome, variants in the mitochondrial DNA, epigenetic changes such as changes in methylation patterns, as well as low-level mosaicism. If one of these conditions is suspected, please order the appropriate test.

Re‐analysis and an updated report can be requested (please contact the laboratory for additional information).

Turnaround time

  • Postnatal cases: test results are reported to the referring physician within 6-8 weeks from the receipt of specimens from all pertinent family members.
  • Prenatal cases: test results are reported to the referring physician within 2- 4 weeks from the receipt of specimens from all pertinent family members.

Specimen Requirements

Accepted samples include whole blood*, buccal swabs, amniotic fluid (direct or cultured), chorionic villus sample (direct or cultured), tissue samples, as well as DNA specimens obtained from other CLIA-certified laboratories.

All specimens should carry two independent identifiers and be shipped at room temperature

*Preferred sample

Forms

Please contact us for additional information (including costs):

Email: pglsupport@cumc.columbia.edu       

Telephone: (212) 305-5631