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Diagnostics Genetics and epigenetics, Omics

Exome Expectations

Our exomes contain roughly 1 percent of our DNA, but 85 percent of disease-causing mutations (1), and now a study has highlighted just how powerful a diagnostic whole exome sequencing (WES) could be.


Published in JAMA, the research details the results of 2,000 patients referred to the Baylor College of Medicine in Texas, US, with suspected genetic disease – mostly pediatric patients with neurological disorders or developmental delay. Twenty-five percent of those patients sequenced received a molecular diagnosis, including detection of rare genetic events and previously unseen mutations. This is a much higher diagnostic rate than that of karyotyping (5–10 percent) and chromosomal microarray (15–20 percent) (2). The researchers believe that 65 of their diagnosed cases would not have been diagnosed correctly by other conventional methods.

Peripheral blood and tissue samples, collected from either probands or their parents, were analyzed using next generation sequencing and compared to a reference sequence: 708 variants in causative genes were found in 504 patients, 57.8 percent of which were novel mutations. Twenty-three patients were also found to have more than one causative mutation, resulting in more complex, blended phenotypes. The diagnosis rate differed depending on phenotype: despite being the smallest group, patients with specific neurological problems, such as seizures, were most likely to receive a diagnosis.

An additional 95 incidental medically actionable mutations (mutations which did not cause the phenotype being investigated, but also clinically important) were found in 92 patients, which included the discovery of genes related to familial breast cancer, Fanconi anemia and familial hypercholesterolemia. To obtain a diagnosis, the team considered the specific variable identified, the gene involved and the clinical case history.

According to the research team, many of the unexplained cases in the study are also likely to have mutations in disease genes that have yet to be discovered, and it’s possible that the information needed to diagnose them could already be waiting in their exome.

WES analyzes only the coding regions of DNA, as opposed to whole genome sequencing (WGS). It also provides broader coverage than other approaches, such as SNP arrays and techniques that only focus on a small number of genes or loci, based on the presentation of the patient. But it isn’t perfect. Sequencing only exons means that WES cannot provide information on splice site or intronic mutations, which occur in non-coding regions. The technical limitations of current WES methods also mean that complete coverage cannot be achieved and some exonic mutations could be missed.

Despite the limitations, the study authors believe that WES represents a cheaper and more available alternative to WGS, while still providing superior coverage compared with some other genetic analysis methods – its diagnostic rate was upheld by both their original study of 250 patients and the much larger cohort (3). In particular, WES could be very useful in certain patients where a genetic disease is suspected but not easily identifiable, because it can allow for analysis of multiple genes in tandem. “For years we’ve known that whole-exome sequencing can identify new disease-causing mutations,” says Yaping Yang, co-author of both studies and a geneticist at the Baylor College of Medicine. “But this puts it on the map as a tool for clinical medicine.”

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  1. B. Rabbani et al., “The Promise of Whole-Exome Sequencing in Medical Genetics”, J. Hum. Genet., 59, 5-15 (2014).
  2. Y. Yang et al., “Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing”, JAMA, [epub ahead of print] (2014).
  3. Y. Yang et al., “Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders”, N. Engl. J. Med., 369, 1502–1511 (2013).
About the Author
Roisin McGuigan

I have an extensive academic background in the life sciences, having studied forensic biology and human medical genetics in my time at Strathclyde and Glasgow Universities. My research, data presentation and bioinformatics skills plus my ‘wet lab’ experience have been a superb grounding for my role as an Associate Editor at Texere Publishing. The job allows me to utilize my hard-learned academic skills and experience in my current position within an exciting and contemporary publishing company.

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