By Lori Solomon, Editor, Diagnostic Testing & Emerging Technologies
Researchers at Children’s Mercy Kansas City cut in half the time needed for rapid whole-genome sequencing (WGS) to diagnose genetic conditions in critically-ill infants, according to a study published Sept. 29 in Genome Medicine. Improvements in the STAT-Seq time included faster sequencing run time, read alignment, and variant calling, cutting the center’s previous 50-hour WGS record to a 26-hour turn-around time (from receipt of blood sample to provisional molecular diagnosis).
"While the cost of WGS has fallen dramatically, it remains too slow to be suitable for guidance in the management of many acute medical conditions," write the authors, led by Neil Miller, director of informatics and software development at Children’s Mercy. "Here we describe second generation STATseq, with improved timeliness, sensitivity, and scalability."
Genomic medicine is transformative for assessment of genetic disease (including rare diseases and those with atypical presentations) because it is capable of rapidly and simultaneously testing all potentially relevant genes, regardless of a clinician’s differential diagnosis.
This study retrospectively re-evaluated parent–child trios enrolled in a research biorepository who received WGS to diagnose monogenic disorders of unknown etiology in affected infants. Infants received rapid WGS if the probable diagnosis was likely detectable by next-generation sequencing and had any potential to alter management or genetic counseling.
Among the most significant improvements:
- Development of an ultra-rapid run mode on the Illumina HiSeq 2500 sequencing instrument cut sequencing time from 25.5 hours (using the rapid run mode) to 18 to 21 hours, with the same quality, quantity, and precision of sequences, but with greater analytic sensitivity (99.5 percent in a 40X genome).
- Edico Genome’s DRAGEN processor (aligner and variant caller) cut data analysis time from 22.5 hours (with CASAVA v1.8.2; Illumina) to 41 minutes. (Several authors report financial ties to Edico Genomics.)
- Replacing manual interpretation and reporting process with in-house VIKING software program saved three hours.
- Optimization of in-house software, RUNES (Rapid Understanding of Nucleotide variant Effect Software) more quickly detects mutations in gene sequences (30 minutes) and saved another two hours.
The researchers say that their initial clinical experience with rapid WGS involved 35 parent–infant trios, with all infants acutely ill, 4 months of age or less, and with a suspected genetic cause of disease. Rapid WGS provided a genetic diagnosis in more than half of the infants (57 percent). Of these receiving a diagnosis, nine of the twenty received a diagnosis that had not been considered in the differential diagnosis. Seventeen of the diagnoses were either of "acute clinical utility" or had "strongly favorable effects on management."
"A randomized, prospective clinical study of rapid WGS is now in progress to ascertain the extensibility of these results to broad NICU populations," the authors write. "Clearly, while the application of rapid WGS for NICU diagnosis of genetic disease appears tremendously promising, translating diagnoses into effective precision medicine is in its infancy.”
For more information on how WGS is transforming the diagnosis of rare diseases, please see the October issue of Diagnostic Testing & Emerging Technologies.