Public Release: 

Study examines type of exome sequencing and molecular diagnostic yield

The JAMA Network Journals

In a sample of patients with undiagnosed, suspected genetic conditions, a certain type of exome sequencing method was associated with a higher molecular diagnostic yield than traditional molecular diagnostic methods, according to a study appearing in JAMA. The study is being released to coincide with the American Society of Human Genetics annual meeting.

Exome sequencing, which sequences the protein­coding region of the genome (the complete set of genes or genetic material present in a cell or organism), has been rapidly applied in research settings and recent increases in accuracy have enabled the development of clinical exome sequencing (CES) for mutation identification in patients with suspected genetic diseases. Early in 2012, the Clinical Genomics Center at the University of California, Los Angeles, launched a CES program with the goal of delivering a more comprehensive method for determining a molecular diagnosis for patients with presumed rare Mendelian disorders (a genetic disease showing a certain pattern of inheritance) that have remained undiagnosed despite exhaustive genetic, biochemical, and radiological testing. Researchers at this center have introduced a new test, called trio-CES, in which the whole exome of the affected proband (first identified individual affected with the disorder among other family members) and both parents are sequenced, according to background information in the article.

Hane Lee, Ph.D., of the University of California, Los Angeles, and colleagues report the results of clinical exome sequencing performed on 814 patients with undiagnosed, suspected genetic conditions at the Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) or as proband-CES (only the affected individual sequenced) when parental samples were not available.

Overall, a molecular diagnosis (with the causative variant(s) identified in a well-established clinical gene) was provided for 213 of the 814 total cases (26 percent). There was a significantly higher molecular diagnostic yield from cases performed as trio-CES (127 of 410 cases; 31 percent) relative to proband-CES (74 of 338 cases; 22 percent) in the overall group of cases.

In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41 percent (45 of 109) for trio-CES cases and 9 percent (2 of 23) for proband-CES cases.

"In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted. Clinical implications of these findings need to be better understood before CES should be routinely adopted," the authors conclude.

(doi:10.1001/jama.2014.14604; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Genome-Scale Sequencing in Clinical Care

In an accompanying editorial, Jonathan S. Berg, M.D., Ph.D., of the University of North Carolina at Chapel Hill, comments on the two JAMA studies that examined exome sequencing.

"Ultimately, it will be essential to know who will benefit from clinical genomic sequencing, including the role of sequencing in a variety of settings, such as oncology, prenatal diagnosis, newborn screening, or population screening in healthy adults. The National Institutes of Health and other funding agencies are supporting a broad portfolio of research projects investigating these and other questions about genomic medicine. In the meantime, physicians should be judicious in considering when to obtain clinical exome sequencing; should effectively communicate the risks, benefits, and limitations of such testing; should be able to clearly communicate the results to patients and their families; and should avoid unnecessarily burdening patients with the cost of such testing if not covered by insurance. The application of genomic sequencing will ultimately contribute to progress in clinical care, from molecular diagnosis to improved outcomes, but there is much to learn before it can be applied more universally."

(doi:10.1001/jama.2014.14665; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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