Similar study of exome sequencing at UCLA produces findings that mirror the diagnostic outcomes produced by researchers at the three Houston organizations

In recent years, pathologists and other clinical laboratory professionals have seen increasing evidence of the benefits of using exome sequencing for clinical diagnostic purposes.

Confirming their initial published findings of a 25% molecular diagnostic rate, researchers from Baylor College of Medicine (BCM), Baylor Human Genome Center, and the University of Texas Health Science Center at Houston have released results of a large sampling of 2,000 consecutive patients.

In this expanded study, published in the November 12, 2014, issue of the Journal of the American Medical Association (JAMA), 504 patients (25.2%) received a molecular diagnosis and 92 patients (4.6%) benefitted from medical intervention to ameliorate or eliminate negative symptoms.

Genome Sequencing to Become the New ‘Family History’

James R. Lupski, M.D., Ph.D., Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics at BCM and coauthor of the JAMA report, believes these latest results “will forever change the future practice of pediatrics and medicine as a whole.”

“It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis,” he said in a BCM news release. “It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent, and the new mutations that contribute to disease susceptibility.”

James R. Lupski, M.D., Ph.D

James R. Lupski, M.D., Ph.D. (pictured above) is the Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics at Baylor College of Medicine, Houston. Lupski, co-author of a large study confirming a 25% molecular diagnostic rate using exome sequencing, predicts genomics soon will be the “new family history” for physicians formulating a differential diagnosis. (Photo copyright Baylor College of Medicine)

This larger study, which was led by Yaping Yang, Ph.D., Associate Professor of Molecular and Human Genetics at BCM, and Christine Eng, M.D., Professor of Molecular and Human Genetics at BCM, replicated the 25% diagnostic rate announced when initial results from 250 cases were published in the New England Journal of Medicine in October 2013.

The study population, mostly children, had clinical whole-exome sequencing performed at a single academic clinical genetics laboratory from June 2012 to November 2013. The authors also provided information on a summary analysis of unselected, unrelated cases completed from November 2013 through Aug. 30, 2014, which brought the total number of cases included in the report to 3,386 patients.

Medical Lab’s Exome Sequencing Brings Patients Relief from ‘Diagnostic Odyssey’

BCM, along with Columbia University and others, have shown exome sequencing’s capability to end the “diagnostic odyssey” that many patients with unknown disorders experience.

“It has been wonderful to watch this very large team of colleagues bridging from the patient in clinic to the very most cutting edge genomic technology to give families answers where previously there were none,” Arthur Beaudet, M.D., Professor of Molecular and Human Genetics at BCM, stated in a news release about the latest BCM findings.

Medical Exomes and the Illumina HiSeq 2500 System

BCM is continuing to refine its diagnostic exome test in an effort to spread its usefulness and reach. In September 2014, BCM began offering so-called “medical exomes.” This sequencing program includes enhanced coverage of more than 3,600 genes, as well as a “lightning exome,” which performs exome sequencing on the Illumina HiSeq 2500 System and reduces total turnaround time from 20 days to less than three days.

“What we really want to do is access unsolved cases from the clinical side and bring them to the research side to solve more of the cases and facilitate discovery,” Donna Muzny, BCM Instructor in the Department of Molecular and Human Genetics, said in a GenomeWeb report. To facilitate this partnership, BCM patients can consent to further sequencing and analysis in a research setting if initial exome testing does not produce a diagnosis.

Matching UCLA Study Compares Trio-CES to Proband-CES

In a separate study, also published in the November 12, 2104, issue of JAMA, researchers from the University of California, Los Angeles (UCLA), compared testing results using trio-clinical exome sequencing (CES), where the patient’s parents also undergo CES, versus proband-CES, where only the patient is sequenced. In their sampling of 814 patients with undiagnosed, suspected genetic conditions, the authors reported that trio-CES resulted in a 31% molecular diagnosis rate versus a 22% using proband-CES. The overall molecular diagnosis rate was 26%.

Will Exome Sequencing Evolve into a Routine Clinical Laboratory Test?

JAMA ran an editorial along side the BCM and UCLA studies that noted the “compelling evidence for the ability of exome sequencing to establish a molecular diagnosis.” It is titled: “Genome-Scale Sequencing in Clinical Care, Establishing Molecular Diagnoses and Measuring Value,” and authored by Jonathan S. Berg, M.D., Ph.D. Berg, however, stopped short of endorsing exome sequencing as a routine clinical test.

Jonathon S. Berg, M.D., Ph.D

Jonathon S. Berg, M.D., Ph.D. (pictured above) noted in a JAMA editorial the “compelling evidence for the ability of exome sequencing to establish a molecular diagnosis,” but he believes further research is needed before genomics will be used as a routine clinical test. (Photo Copyright University of North Carolina School of Medicine)

“It is difficult to discern the overall performance (clinical sensitivity and clinical specificity) of exome sequencing from these data . . . further details about the performance of exome sequencing will be needed as its use as a routine clinical test is contemplated,” he wrote.

The benefit of exome sequencing as a tool for diagnosing rare genetic disorders is rapidly being validated through new research data and improved testing success rates. Such progress could set the stage for genomics to become the new ‘family history’ for physicians formulating differential diagnoses in hard-to-solve cases. As this happens, there will be new opportunities for pathologists and molecular Ph.D.s to add value to physicians through consultations and similar professional services.

—Andrea Downing Peck

Related Information:

Whole Exome Sequencing Closer to Becoming ‘New Family History’

Researchers at Columbia University Report How Exome Sequencing Helped Diagnose Patients with Unknown Disorders

Clinics Unroll Genome Tests for Undiagnosed Disorders

Exome Sequencing Found to Accelerate the Diagnostic Process of Several Diseases

Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders

Genome-Scale Sequencing In Clinical Care, Establishing Molecular Diagnoses and Measuring Value

Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing

Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders