Research Report 2019_20

David Bick, MD / The Smith Family Clinic for Genomic Medicine

Best practices for clinical whole-genome sequencing

Advances in next-generation sequencing technology are revolutionizing rare genetic disease diagnosis. The most comprehensive sequencing technology, called whole-genome sequencing (WGS), is a powerful clinical tool for detecting known and potential disease-caus- ing DNA variations. However, chromosomal microarray analysis and whole-exome sequencing, not WGS, are currently indicated as first-tier tests for the diagnosis of many rare genetic diseases.

Through his role at The Smith Family Clinic for Genomic Medicine, Bick has witnessed firsthand the value of using WGS to solve cases of misdiagnosed and undiagnosed genetic disease. Patients referred to the clinic have usually been on a diagnostic odyssey— searching for answers for many years, visiting dozens of doctors, and some receiving misdiagnoses. WGS al- lows geneticists like Bick to look at all of the patient’s genes at once, greatly increasing the likelihood of making a diagnosis. However, a lack of standards for best-in-class clin- ical WGS presents a barrier to its widespread adoption. Because of HudsonAlpha’s expertise using WGS as a clinical test, Bick was chosen to serve as a member of the Medical Genome Initiative (MGI), which consists of genomic medicine experts who work tirelessly to over- come this barrier. The MGI aims to expand access to high-quality clinical WGS for the diagnosis of genetic diseases through the publication of common laboratory and clinical best practices. In a paper published in December 2020, Bick and the MGI team presented consensus recommenda- tions and suggested best practices for the analytical validation of clinical WGS for the diagnosis of germline genetic disease 1 . Analytical validation demonstrates the accuracy, precision, and reproducibility of a test, which is abundantly important for a test returning results as complicated as WGS. Based upon their practical experi- ences and discussions amongst the group, they present- ed key statements describing their recommendations for analytical validation of clinical WGS. Their recommendations ranged from the type and number of variants analyzed and reported in a WGS test to the type of reference standards that should be used to validate each run of a WGS test. Importantly, the group endorsed the use of clinical WGS as a viable first-tier test for rare disorders, and suggested that it replace chromosomal microarray analysis and whole-exome sequencing as a first-tier test. Bick and the MGI team hope that the practical advice put forth in the publication will encourage other laboratories to introduce WGS into

Dr. Bick working on interpreting a whole genome sequence on HudsonAlpha Codicem software.

David Bick, MD, believes that clinical WGS is ready to take over as a first-tier test for rare genetic disease diagnosis. Bick is a leader in the genomic medicine field and serves as the chief medical officer and a faculty investigator at the Institute, the medical director of The Smith Family Clinic for Genomic Medicine LLC , and a laboratory director in the HudsonAlpha Clinical Services Laboratory, LLC .


HudsonAlpha Institute for Biotechnology

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