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UCL Team Develops Clinical Pediatric Whole-Genome Sequencing Workflow for NHS Setting

NEW YORK (GenomeWeb) – A University College London-led team has developed a pediatric whole-genome sequencing workflow that fits within a UK National Health Service diagnostic setting.

As its 100,000 Genomes Project winds down, the UK plans to begin offering diagnostic whole-genome sequencing this fall, starting with patients with rare diseases or certain cancers. Teams in the US and elsewhere have previously reported that rapid sequencing can help quickly diagnose some infants with suspected genetic disease.

However, the authors of the new study published today in the Journal of Medical Genetics argued that previous efforts often relied on approaches that aren't compatible with standard diagnostic laboratory procedures. To address this i, the researchers built a workflow that could be implemented in an NHS setting and could give a molecular diagnosis for 42 percent of its cohort, within a median seven days.

"An essential goal of this study was to develop a workflow integrated within an existing service laboratory that could be adopted by other diagnostic centers," senior author Hywel Williams from UCL Great Ormond Street Institute of Child Health and his colleagues wrote in their paper.

To do that, Williams and his colleagues used off-the-shelf products and configured their approach to fit within standard practices.

For instance, they sequenced the whole genomes of the 24 trios in their study using either the Illumina NextSeq 550 or HiSeq 2500 platforms. They then used a Genalice module for mapping and variant calling, the Qiagen Ingenuity Variant Analysis software to identify rare variants likely to have a functional effect, and the 1000 Genomes, Exome Aggregation Consortium, and Exome Variant Server databases to determine the frequency of the variants and gauge which could be deleterious.

At the same time, the researchers used a standard template to gather clinical and family history, which was then captured as Human Phenotype Ontology (HPO) terms.

For each patient, the researchers separated their analyses into three phases. In the first phase, they focused on genes that were likely to be implicated in the patients' conditions based on gene lists generated using the HPO terms and the Genomics England Panel App, Phenotips, and the Online Inheritance in Man Gene Map.

If that didn't yield results, the second phase expanded the analysis to genes from the Developmental Disorders Genotype-Phenotype database and the OMIM Morbid genes. If that, too, came up empty, the third phase examined variants in any genes with evidence for causality.

A genomic multidisciplinary team then reviewed the variants, which were scored according to American College of Medical Genetics and Genomics guidelines, and reported to physicians. Diagnostic findings were validated using Sanger sequencing.

Overall, 10 children, or 42 percent of the cohort, received a molecular diagnosis through this workflow. All these diagnoses, the researchers noted, were obtained in phase I analyses. These diagnostic variants included four de novo mutations, three pairs of compound heterozygous variants, and three homozygous variants.

The analysis time was also fairly swift: it took a median seven days to perform the workflow. This, they noted, reflected "real-life" situations based on standard working hours and included technical delays.

The diagnoses also led to a change in clinical management for three patients. For example, one patient with renal failure had a de novo WT1 mutation, which the researchers said not only explained the patient's renal phenotype but also informed the need for a bilateral nephrectomy to prevent the development of Wilms tumors.

They further estimated the cost of running a rapid WGS trio to be between £6,105 ($8,037) and £8,605 ($11,328).

"Rapid WGS can be used to diagnose and inform management of critically ill children within the constraints of an NHS clinical diagnostic setting," the researchers concluded.