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Submitted by Nicholas Johnson, MD
Many inherited neuromuscular (NM) diseases, such as Charcot-Marie-Tooth disease or limb girdle muscular dystrophy require panels or algorithms for genetic testing. Despite these panels, many patients remain without a confirmed genetic mutation. In the absence of the characteristic signs and symptoms that yield a single genetic diagnosis, such genetic panels are very expensive and time consuming.
Whole genome sequencing and whole exome sequencing (WGS/WES) are becoming increasingly available for the diagnosis of genetic disorders. These techniques either sequence the entire genome (WGS) or all of the translated regions (WES). Such techniques would allow a clinician to evaluate every single gene of interest at once, and potentially identify new pathogenic mutations.
The lower cost of these techniques compared to current methods is touted as a key benefit of the technology. In particular, WES is already widely implemented in some NM clinics for undiagnosed cases or non-specific phenotypes with multiple potential mutations (e.g., limb girdle muscular dystrophies). However, mechanisms for interpretation of the data and analysis of rare variants remain a work in progress. The American College of Medical Genetics (ACMG) has recently identified standards to process the incidental genetic findings that occur with these techniques. This study seeks to identify the implications for patients and health care costs of WGS.
About the Study
In this study, the authors performed WGS on 12 adults without evidence for inherited disease. To evaluate the reproducibility of the WGS, it was performed twice in nine patients. Depending on the sequencing platform, 10-17% of genes associated with inherited disease or ACMG reportable genes were not covered sufficiently for genetic variants. The concordance for the two sequencing platforms was highest with the common variants, but only moderate for genetic variants that were candidates for inherited disease risk. The phenotyping software identified 90 to 127 genetic variants in each participant. The authors estimated that they spent 54 minutes per variant, and the total cost for variant interpretation was $14,815. Each patient harbored 2-6 genetic variants associated with increased disease risk, and genetic variants that would change drug dosing or administration were identified in 11. Once the results were provided, patients had a median of 1-3 additional referrals or diagnostic tests, at a median cost of $626-$773.
For the NM physician, deciding on which genetic test to order is a common quandary. The advent of high-throughput WES or WGS holds promise as a “one size fits all” approach that will quickly and cheaply assess all possible genetic variants in patients with unexplained NM disease. This article raises several key concerns about our ability to support the costs and effort required for such tests.
In addition, for several of the rare conditions, there may not be adequate coverage with some of available sequencing platforms, which will likely improve with current technological advances.
About the News Science Editorial Board
The board helps to highlight significant, timely science news items for AANEM members. It reviews articles in journals and websites, identifies newsworthy items in the field each month, and writes article summaries.
Zaeem Siddiqi, MD, PhD (chair); Shan (Sarah) Chen, MD, PhD; Brent Goodman, MD; Ileana Howard, MD; Nicholas Johnson, MD; Carlos Luciano, MD; Andrew Tarulli, MD; Leigh Maria Ramos-Platt, MD