CHARLOTTE, NC (GenomeWeb News) – Baylor College of Medicine's whole-exome sequencing program, launched by the institute's Whole Genome Laboratory late last year, is showing clinical utility for diagnosing a range of rare and more common genetic conditions, attendees at the American College of Medical Genetics and Genomics annual clinical genetics meeting heard here this weekend.
During a session on practical implementation of next-generation sequencing in molecular diagnostics, Christine Eng, DNA director of BCM Medical Genetics Laboratories' diagnostic laboratory, described the approaches her team is using to interpret and report whole-exome sequencing data in a diagnostic setting.
She also offered several examples from several cases in which disease related and/or other medically actionable mutations have been identified in patient samples using the test.
BCM officially launched its clinical whole-exome sequencing program in mid-November of last year.
When deciding if and how to undertake whole-exome-based diagnostic testing, Eng said the group drew on the experiences of other groups, including researchers from the National Institutes of Health Undiagnosed Diseases Program, who presented preliminary results from their integrated diagnostic testing effort in a Genetics in Medicine study published online last September.
Based on results described in that study, the BCM group anticipated that they would be able to identify common, rare, or novel disease-related mutations for roughly a quarter of the cases tested.
In their first few months of exome-based testing, Eng said the lab has received around 100 samples. Of the nearly three-dozen samples completed to date, the group has been able to find diagnostically relevant mutations around one-third of the time.
The use of whole-exome sequencing in the diagnostic arena presents some distinct challenges compared to other genetic tests, Eng cautioned, including an increased reliance on getting accurate and complete information about a patient's clinical phenotype and family history. Interpreting and reporting the results of the tests is also complicated by the fact that genetic mutations often turn up in several genes, including some with clear ties to a condition of interest and others with ties that are more tenuous.
To deal with such complexities, Eng said her diagnostic laboratory is currently generating two reports for each patient.
The first, a focused report, outlines the deleterious mutations that have been detected and validated in disease genes, variants of unknown significance found in genes related to a patient's phenotype, and medically actionable mutations.
Patients also have the option of receiving information on autosomal recessive carrier status for certain conditions and pharmacogenetic loci in the focused report, Eng noted.
In another, expanded report, the lab describes variants of unknown significance and apparently deleterious mutations detected in the exome sequence that don't seem to be related to the disease at hand. The latter designation can change with time, Eng said, noting that the group has already encountered a situation where a mutated gene with no apparent links to the condition of interest was eventually implicated in the disease based on studies that came out after the initial sequence interpretation.
While all of the patients receive the focused report, clinicians are also briefed on expanded report results so that patients can be made aware of the risks and benefits of receiving this additional genetic data.
While the Baylor diagnostic lab is currently providing whole-exome-based diagnostic reports on paper, Eng said she envisions a web-based system for reporting whole-exome or genome sequence results in the future.
Such a system would make it possible to provide crucial information in a compact report, while also offering hyperlinks for clinicians to access additional information, if necessary, she explained. It would also let providers and patients view versions of the information that is tailored to them, which could be updated over time as the interpretation of some mutations and their roles in disease improves.
For their part, Eng said the Baylor lab plans to offer reinterpretation of whole-exome sequence data after a year as a means of keeping results as up to date with the current literature as possible. They will also consider earlier reinterpretation of sequence data and/or Sanger validation of VUS from the extended report when clinicians request this information.