Vol. 21 • Issue 9 • Page 56
Focus On: Genetics
In the field of molecular genetics, the ability to sequence every human gene represents the brass ring of molecular testing. With the arrival of new technology and the drop in cost of sequencing, the clinical exome has arrived-but not without challenges.
Whole exome sequencing was first launched commercially by Ambry Genetics in late 2011. Other academic and commercial labs quickly followed. The ability to launch this complicated test and provide medically relevant results relies heavily on having a firm foundation in next-gen sequencing technology. Early adopters of this technology are industry leaders in generating data and developing methods for alignment, variant calling and analysis, and have the experience needed to handle the nuances of exome sequencing and reporting.
Today, numerous out-of-the box software packages promise fast results, but these promises often come saddled with heavy compromises – especially when it comes to reporting. Custom in-house software design can surmount many of these challenges but requires a significant investment in bioinformatics infrastructure. Even then, the best bioinformatic analysis cannot replace the hands-on time of a medical genetics team who carefully analyzes each variant call both for pathogenicity and relevance to the clinical phenotype, the final critical ingredient to a successful exome test.
To date, the clinical exome test has primarily focused on diagnosis of children and adults who are strongly suspected of having a Mendelian disorder either based on clinical features or family history. Prior to exome sequencing, the molecular basis for fewer than half of these disorders was known, but that number is growing rapidly through both research and clinical exome testing.
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One of our first exome cases was a family in which two brothers, now in their 20s, suffered from severe intellectual disability. A bevy of testing over the years had failed to inform the underlying etiology of their condition. Within two months of receiving blood samples from this family, a diagnosis of autosomal recessive mental retardation, secondary to mutations in the gene ELP2, was reached.
In follow-up discussions, the mother admitted to submitting their sample with little hope, never really expecting an answer. When the results were delivered, she cried with joy: at long last she had clarity.
Now, the couple not only know that their risk of having another affected child is high – 25% – but also understand that their recently-married daughter has only a very minimal risk of having a similarly affected child, a risk that could be even further reduced by a simple test on her husband.
An Evolving Field
The addition of next-gen sequencing to a clinical lab workflow is no simple task. While analysis of DNA variants once plagued a minority of sequence analysis, the converse is now true. To counteract this, a focus on automation can free up skilled personnel to spend more time in data analysis. Laboratorians with bioinformatics expertise are extremely valuable in the next-gen lab and can significantly reduce the hands-on time for sequence analysis. This also allows the bioinformatics department to focus on development and validation of methods for sequence analysis and variant interpretation, rather than daily workflow (see Figure).
Clients can be surprised by the complexity of results and frequency of variant reports. Clinically-trained staff, such as genetic counselors and board-certified directors, fill a critical, growing role in assisting in test selection and interpretation of results for providers and their patients.
Next-gen sequencing has rapidly spread to the lab where the power of this technology necessitates reformatting traditional models. This often necessitates a significant investment in technology and infrastructure. With the right tools and a new paradigm for molecular testing, a bright future for genomic medicine is clearly on the horizon.
Elizabeth Chao is director of translational medicine at Ambry Genetics, Aliso Viejo, Calif.