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More precise diagnoses will encourage pathologists and clinical laboratory professionals to consider using exome sequencing for clinical diagnostic purposes

Having sequenced the exomes of 150 patients to diagnose unknown disorders over the past year, physicians at Columbia University (CU) used that information to make decisive diagnoses in one-third of the cases. It is evidence from one of the nation’s pioneering gene-sequencing programs that such data can improve how physicians identify disease.

Findings from Exome Sequencing Program Noteworthy for Pathologists

Pathologists will find it noteworthy that some of the patients in the exome-sequencing program had been tracked for years at CU without a definitive diagnosis. This is why clinicians at the academic center in New York City see value in exome sequencing for selected patients.

For more than a year, doctors at Columbia University have tested the exome’s capability to provide a correct diagnosis for patients with suspected genetic disorders of unknown origins. The primary goal of the program is to prove that sequencing the exomes of these patients is both clinically useful and cost effective in guiding physicians to a correct diagnosis.

Exome Testing Provided Diagnosis in One-Third of 150 Patients Tested

So far, Columbia clinicians have completed exome sequences for 150 patients. The resulting information enabled them to make decisive diagnoses for one-third of the cases, reported an article published by “I think it’s an incredibly powerful tool,” said Wendy Chung, M.D., CU Associate Professor of the Clinical Genetics Program. She was quoted in the GenomeWeb report.

Among the first 150 genome sequencing cases were patients Chung had followed for years without the ability to make a definite diagnosis. Of these patients, Chung said that she had “a strong clinical sense that there was an underlying genetic problem.” A significant number of these cases suffered from neurological conditions, but also heart conditions, syndromic birth defects and hearing loss.


Wendy Chung, M.D. (pictured), Associate Professor for Columbia University’s Clinical Genetics Program, is heading a study aimed at proving the medical utility and cost-effectiveness of exome sequencing as a first-line diagnostic test. She believes this is essential in ensuring insurers continue to pay for it. (Photo copyright New York-Presbyterian Hospital.)

The Columbia team was unable to identify a disease-causing mutation in about half of the test subjects. “This technology clearly is not perfect,” said Chung. She explained that, in these specific cases, the exome might be incomplete or the mutation might reside in non-coding regions of the genome.

In cases where the exome failed to reveal the genetic mutation, Chung and colleagues are following up with whole-genome sequencing. Even sequencing the whole human genome may not provide the answer due to the lack of reference genomes available to interpret mutations in regions outside the exome, or the disease may have non-genetic causes, she pointed out.

Many of the successful diagnoses were for well-known genetic disorders, in which the mutated gene had already been associated with the disease, but did not fit the textbook description.

Exome Test Revealed New Gene and New Disease in One-Fourth of Cases 

In about one-fourth of cases, CU clinicians identified a new gene as the probable cause of a new disease type, Chung said in the Genomeweb report. For some patients, clinicians were able to identify another family with the same disorder—sometimes carrying the exact same mutation in the same gene. This was accomplished mostly through literature searches and networking with doctors internationally.

Chung further noted that a centralized database of genetic mutations would facilitate finding other families that match these cases. While the National Institute of Health’s ClinVar database might serve this purpose for clinical laboratories, it does not serve the needs of research laboratories, which are “sitting on a lot more genomic data than the clinical laboratories,” Chung added.

Researchers Identifying Most Comprehensive Sequencing Facilities 

As part of the exome testing process, researchers at Columbia University compared genomic services provided by different laboratories to identify genomic sequencing facilities that offer the most efficient and comprehensive services. Therefore, patient samples were sent to four different laboratories:

Ambry Genetics

Baylor College of Medicine Medical Genetics Laboratories


Columbia’s own Personalized Genomic Medicine Laboratory

“The biggest problem that I’m seeing is one of capacity, declared Chung, noting that turnaround time for exome tests has been increasing. “Everyone is starting to realize how valuable this [exome testing] in fact is.” She stressed the importance of identifying efficient genome testing providers, pointing out that inefficiency might hamper wider adoption of exome testing.

The clinical team at Columbia found that gene-sequencing services differed in several ways, noted the Genomeweb report. Some genomic service laboratories allow physicians to opt out of secondary findings, which Chung noted is a preference of many Orthodox Jewish patients. Other labs offer to re-analyze data after a period of time because of new research that might now link additional genes to a patient’s disease. She said this was helpful in solving two cases in which no answer had been found initially.

Differences in Labs Sequencing Exomes

Chung did call attention to one important difference between exome-sequencing labs. Some of these labs will also sequence parents or other family members—such as siblings—who are affected in the gene sequence. Noting that this increases the sensitivity for de novo and rare inherited mutations, she remarked, “We found it more helpful to work with laboratories that sequence the [exomes of] parents upfront.”

Additionally, some laboratories were easier to work with in terms of billing policies and how insurance is handled. Overall, the Columbia team said it experienced the best service from GeneDx. That is because this lab offers re-analysis after a year, includes family members in the analysis, and handles insurance issues efficiently.

Chung Optimistic About Future of Exome Testing

In the future, Chung predicts that exome testing will be used earlier in the diagnostic process than today. She noted that, to date, exome testing has been used after patients had gone through other diagnostic processes, including panel testing, micoarrays, and metabolic workups.

“Increasingly, as we realize how useful it can be, it’s [exome sequencing] becoming more of a first-line test,” observed Chung. “Now that patients and other providers are hearing about our success, many patients with a wide variety of familial conditions that are thought to be genetic… will come asking for help.”

Going forward, Chung stressed the importance of convincing health insurers that the exome sequencing test, is worth the cost of a few thousand dollars. “I can easily see from some back-of-the-envelope calculations we have done… how it changes medical care, how we avoid additional diagnostic testing, other procedures, [and prevent] additional affected children—but more evidence is needed,” she pointed out in the Genomeweb article.

To prove the test’s clinical utility and cost effectiveness, Chung is collaborating with health economists at the Columbia Mailman School of Public Health and others to collect data on how the exome is used, how the results affect patients, what types of further tests were avoided, and how the test changed patient care.

—by Patricia Kirk

Related Information:

Columbia’s First 150 Clinical Exomes Boost Diagnoses; Utility, Cost-Effectiveness Study Underway

Illumina Asserts Its Claim of a $1,000 Whole Human Genome, But Is Gene Sequencing Ready for Use by Clinical Pathology Laboratories?

New Industry Emerging to Provide Cloud-based Computing Firepower Needed for Big Data Genomic Analyses of Healthcare and Medical Laboratory Information

New Research Findings Determine that ‘Dark Matter’ DNA Does Useful Work and Opens Door to Develop More Sophisticated Clinical Pathology Laboratory Tests