Clinical Analysis of genetic variation in the context of symptoms and family history

Whole exome sequencing (WES) can be used to identify the underlying molecular basis of a genetic disorder in an affected individual who has exhausted all other currently available genetic testing options. The XomeDx test is different from other types of genetic diagnostic tests in terms of the number of genes that are sequenced simultaneously. The XomeDx test targets the protein-coding regions of the human genome, which represents ~20,000 genes and accounts for approximately ~2% of all human genetic material.¹ To date, exome sequencing has been used to find novel mutations and genes associated with Mendelian disorders, as well as clarify the cause of atypical presentations and rare diseases.^2,3,4

When is this test useful?
This test is useful when a patient has gone through all the routine diagnostic tests and does not yet have a definitive molecular diagnosis. If we receive a request for testing for a patient who has not gone through previous diagnostic testing, we may recommend other tests first to minimize cost and maximize efficiency in obtaining a diagnosis. Our goal is to offer the XomeDx testing service only when clinically appropriate and when a diagnosis cannot be made by other more direct methods.

 

What GeneDx offers

1. Technology Platforms:

   1. Exome sequencing and copy number variant (CNV) analysis
   2. mtDNA sequencing and deletion analysis
2. Bioinformatics pipeline to identify clinically-relevant variation
3. In-house team of over 30 geneticists and genetic counselors specializing in rare inherited diseases
4. Case review and management by Sherri Bale, PhD, experienced clinical geneticist.
5. Cost conscious testing. Dr. Bale will review each case personally and start with the most efficient and cost effective approach based on clinical symptoms, family history, and previous testing performed at GeneDx or elsewhere.

Why should you choose GeneDx over other labs?
Genetic variation in humans includes sequence variations in the nuclear and mitochondrial genome as well as copy number variations. Most labs offer only technical sequencing of the nuclear exome. They do not evaluate CNVs or the mitochondrial genome, and they do not analyze or interpret the data in the context of the patient’s clinical and family history. GeneDx is the only commercial laboratory that has all the technologies as well as the breadth and depth of clinical expertise necessary to identify and interpret the entire spectrum of genetic variants.  

What can a patient do with a positive result?

Similar to most genetic tests, a positive result can provide information for both the patient and the entire family. A diagnosis can provide prognostic information, allow for tailored health surveillance and prevention, may suggest specific treatments, allow for networking with other patients with a related diagnosis, access to expert clinicians and researchers, and provide important information to identify other family members at risk. A result can allow families to make informed reproductive choices and provides a means to have healthy children who do not have the genetic condition, through the use of prenatal testing or pre-implantation genetic diagnosis.

 

Does health insurance cover this test?

GeneDx has significant experience billing insurance for diagnostic testing in rare inherited diseases. Since the exact test(s) performed will vary by situation, we may be able to bill certain tests to insurance but not others. As the exome sequencing test has never before been billed to insurance, we do not yet know if it will be covered. We will update our billing policies as we learn more.

 

What are some limitations of this test?

Similar to other genetic tests, this test has several important limitations:

1. Current exome sequencing procedures do not capture the entire exome. At this time, the efficiency of capture is about 95% and while we keep working to improve the amount of sequence captured for analysis, it is possible that the region of a patient’s mutation could be missed
2. The test does not attempt to sequence the non-coding regions of the genome. Although not common, mutations can be located in regulatory regions or other parts of the genome not included in this analysis. We may find rare genetic variations that are not interpretable at this time. Even though a lot is known about human genetic variation, there is much more that is not yet known. If we identify rare variations in our analysis that have never been observed before, we may not be able to provide a full interpretation of the data today, although we anticipate that knowledge will continue to become more complete, allowing better data interpretation with time.
3. It may be necessary to analyze additional members of the family to better interpret the findings on the patient.

 

How can this test be ordered?

Please use the submission form link at the top of this page to download. It is necessary to discuss any XomeDx request prior to sending a specimen. Please use the Contact Us link on our website, e-mail us at genedx@genedx.com or call GeneDx at (301)-519-2100.  

References:

1. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011 Sep 27;12(11):745-55.
2. Ku CS, Naidoo N, Pawitan Y. Revisiting Mendelian disorders through exome sequencing. Hum Genet. 2011 Apr;129(4):351-70. Epub 2011 Feb 18.
3. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010 Sep;42(9):790-3. Epub 2010 Aug 15.
4. Singleton AB. Exome sequencing: a transformative technology. Lancet Neurol. 2011 Oct;10(10):942-6.