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Is exome sequencing a form of clinical diagnosis test ?

Someone with no background in Biology, would get confused about how exome sequencing or clinical diagnosis are related or even what exome sequencing even is. Let’s first start with understanding exome sequencing. We all know something about genome sequencing. Genome Sequencing determines the sequence of a DNA in our body which is unique for each one of us whereas, Exome is comprised of genes which encodes for all the proteins in our body and we know how important those proteins are to perform multiple functions in our system. Thus, determining the DNA sequence of these protein-coding segments of genes is nothing but exome sequencing.

Exome sequencing a form of clinical diagnosis test

Sequencing of exomes gives us information on the disease-causing genetic variations which could be further studied to identify a disease.

Currently, we read in multiple places that exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases. People could even assume that exome sequencing is a diagnostic test. But is it accurate to assume that? Instead, we can say that clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients and this is where clinical diagnosis will come into picture. Clinical diagnosis is based on every patient’s medical history, laboratory tests, family history, and imaging studies which are performed by a physician with an expertise in this field. To diagnose any patient with such disease-causing variant, genotype-phenotype correlation is important.

There are actually two clinical situations where exome sequencing is applied. First, in clinical diagnoses, which we have already discussed. When a physician orders for cytogenetic analysis and gene panel testing on the basis of suspicion it further helps in the detection of any hereditary diseases. For example, when they detect hereditary breast and ovarian cancer in a young woman with bilateral breast cancer.

Second situation occurs more often when the test is performed to detect a possible genetic cause of an etiologically heterogeneous condition such as intellectual disability or epileptic encephalopathy.

In such situations, the probability of finding the disease-causing variant is very low and there are higher chances of false positive results than the test results from a suspected clinical diagnosis, i.e., the first clinical situation. These clinical test results from the laboratories only provide the classification on the already detected variants and refrains from diagnosing a disease. For classifying the variants, there are few guidelines by The American College of Medical Genetics and Genomics (ACMG) that has categorized them into 5 categories. These categories are like the ranking which could tell us if the variants detected are disease- causing or not. :

  • “Pathogenic”;

  • “Likely pathogenic”;

  • “Likely benign”;

  • “Benign”;

  • “Uncertain significance”;

Benign or likely benign variants are usually inherited from the parents of the person affected. Let’s take an example where we find a variant R114W on HNF4A gene by exome sequencing which confirms Type 2 Diabetes and Maturity-Onset Diabetes of Young people (MODY) in a 25 years old woman with a family history of the same. However, it would be wrong to say that another woman of the same age, having the same variant has diabetes, because at present she shows normal glucose levels while also not having a family history of diabetes. The risk of developing diabetes will be there due to the presence of the variant but it will be much less. In conclusion, it is important to understand that exome or genome sequencing are not diagnostic tests. Diagnosis must be performed by a physician who can assess genetic variants in the context of all of a patient clinical features and their consistency with the full spectrum of clinical manifestations that occur in the disease being considered.


Friedman, J. M., Jones, K. L., & Carey, J. C. (2020). Exome sequencing and clinical diagnosis. JAMA, 324(7), 627-628.

Arts, P., Simons, A., Al Zahrani, M. S., Yilmaz, E., Al Idrissi, E., Van Aerde, K. J.,

Hoischen, A. (2019). Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies. Genome medicine, 11(1), 1-15.

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