Out of the lab, into the hospital

The article, titled “Factors influencing success of clinical genome sequencing across a broad spectrum of disorders,” was published online in Nature Genetics on May 18.

The WGS500 study is “a collaborative project between the Wellcome Trust Centre for Human Genetics, the BRC Genomic Medicine Theme and the technology company Illumina with the aim of evaluating the clinical utility of whole-genome sequencing across a number of human diseases,” as noted on the Wellcome Trust Centre for Human Genetics website. One of the main goals is to determine if genome sequencing has potential in a standard hospital setting to inform and improve patient management. The study, conducted by researchers from the University of Oxford and Illumina, has led to the discovery of more than 10 new genes for a variety of diseases, including inherited cancers, blood disorders, epilepsy and muscular or developmental conditions. Some 3,000 patients have been tested globally for mutations in the genes uncovered by this work.

For this initiative, “Proposals were invited from clinicians for cases where standard genetic tests had proved negative or where no test was available. The genomes of 500 patients and family members were sequenced, spanning a range of diseases including Mendelian disorders, severe and early-onset immunological conditions and cancer, with the hope of identifying variants in novel genes or pathways to inform diagnosis, prognosis and reproductive risk, or influence treatment selection.”

The study featured the sequencing of 217 people from 156 independent cases or families with a wide range of disorders who, in previous screening, had not had any pathogenic variants identified.

“We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy,” the abstract notes. “Overall, we identified disease-causing variants in 21 percent of cases, with the proportion increasing to 34 percent (23/68) for Mendelian disorders and 57 percent (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only four were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.”

Some of those challenges, the authors pointed out in the paper, include “cost, speed of delivery, sensitivity, specificity and heterogeneity in variant detection, ambiguities and errors in variant annotation, a substantial informatics burden and the difficulties posed by incidental findings.”

In addition, the team had to develop novel ways to analyze the massive amount of data that results from WGS. Prof. Gil McVean, senior author on the study, commented that “Bringing together the statistical, computational and clinical knowledge needed to analyze and interpret such vast and complex data in real-time is an exciting, but substantial, challenge.”

“Although challenges remain, this study represents an important step in translating the scientific revolution in genetics into improved patient care. So whilst the first human genome sequence took 10 years to complete, cost billions and involved thousands of scientists, we can now look forward to the prospect of genome sequences being provided for £1,000 and in a few days, for NHS patients across the UK,” Prof. Peter Donnelly, director of the Wellcome Trust Centre for Human Genetics and co-leader of the study, said in a press release.

The WGS500 project has led to papers that shed light on the genetic nuances of a variety of diseases, including mutations that cause coronal craniosynostosis, a predisposition to colorectal adenomas and carcinomas, cognitive and motor development impairment, congenital myasthenic syndromes and congenital dyserythropoietic anemia type I.

“Whole-genome sequencing has enormous potential to transform the care of patients in the 21st century and, as shown in this study, can offer families hope for a definitive diagnosis where standard genetic testing has drawn a blank,” commented Dr. Michael Dunn, head of Genetic and Molecular Sciences at the Wellcome Trust. “However, integrating this kind of individual screening into routine clinical care is not without its difficulties, and we will need concerted efforts and resources to enable accurate and meaningful interpretation of genomic data for patient benefit.”