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Medical Genome Initiative Develops Best Practices, Standards for Clinical Whole-Genome Sequencing


NEW YORK — The Medical Genome Initiative, a consortium of research and healthcare organizations founded by Illumina, has developed a set of best practices and standards that aim to further the use of whole-genome sequencing as a clinical diagnostic tool.

While whole-genome sequencing has become a key research tool, there are still barriers to its wider adoption in the clinic. MGI, which was established about three years ago, brings together nine different organizations from across North America to pool their expertise to generate best practices, including recently published guidelines for interpreting and reporting findings from clinical whole-genome sequencing tests. The most recent guidelines emphasize the importance of combining phenotype- and genotype-driven evaluations of sequencing findings as well as keeping up to date on what types of variants sequencing platforms are positioned to detect.

"The desire was to bring the community together to establish best practices in whole-genome sequencing for clinical purposes," said MGI steering committee member Heidi Rehm from the Broad Institute and Center for Genomic Medicine at Massachusetts General Hospital, adding that the initiative aimed to "convene parties that were offering this in their own laboratories and bring them all together so that we could define the best approaches."

The group's steering committee identified key parts of whole-genome sequencing it thought would benefit from best practices or other guidelines, such as test requisition, analytical validity, and clinical utility. MGI has already issued best practices for two of these, analytical validation and measuring clinical utility of genome sequencing.

The steering committee includes representatives from each of the nine groups involved — Baylor Genetics, the Broad, Illumina, the HudsonAlpha Institute for Biotechnology, the Mayo Clinic, the New York Genome Center, Rady Children's, the Hospital for Sick Children, and Stanford Medicine. Rehm noted that although Illumina formed the group, it does not directly fund the initiative. Illumina has aided in organizing meetings and does provide some support staff to the initiative.

While other organizations, like the American College of Medical Genetics and Genomics, also have issued guidelines — in 2021, ACMG published an update to its gene list for reporting clinical sequencing secondary findings as well as recommendations calling for exome or genome sequencing as a first- or second-tier test for children with intellectual disability — Rehm said that MGI can complement those efforts and focus even more on clinical genome sequencing, while providing additional, practical details. For instance, MGI has included results from its informal members survey in its publications, as well as sample forms or other resources or tools they use.

"We can be specific to the genome; we can fill in gaps that aren't already covered by our field," Rehm said.

In its latest set of best practices, published in NPJ Genomic Medicine last month, MGI tackled the interpretation and reporting of clinical whole-genome sequencing tests. One of its key recommendations is that the analysis of clinical whole-genome sequencing incorporate both genotype- and phenotype-driven analyses, as they serve different purposes.

A genotype-focused analysis, for example, would examine all types of suspicious variants that could be classified as pathogenic or likely pathogenic. In that way, genes that might not have otherwise been examined are given a closer look because, for instance, a de novo variant was spotted there. This approach could then identify unexpected genetic disorders or known genetic disorders that have unusual presentations.

A phenotype-focused analysis, meanwhile, would focus on specific genes related to the patients' phenotype. For instance, if the patient has cystic fibrosis, any variant found in the CFTR gene, even one that has never been seen before, should be evaluated.

"You want to really be diligent on both of those approaches," Rehm said.

At the same time, the guidelines noted the importance of communication between ordering providers and labs performing the testing. Such communication can help gauge whether a finding by the lab matches the patient's clinical presentation, as well as vice versa. It can also inform which tests — both genetic and non-genetic — should be used in addition.

The recommendations further highlight that exome and whole-genome platforms may currently be better able to capture certain types of genomic variation than others, which also affects their diagnostic potential. Both exome and whole-genome platforms have high platform maturity and diagnostic potential when it comes to identifying SNVs, but for other variant types, such as repeat expansions or short tandem repeats, improvements are still needed.

MGI has other best practices in the works, with groups set up to provide guidance on patient selection or who might benefit the most from whole-genome sequencing as a first-tier diagnostic test, as well as on data management or how to best store clinical genomic data.

One other area the group is addressing are variants of uncertain significance. One working group is currently tackling the question of whether whole-genome sequencing might generate more VUS than exome sequencing and lead to more downstream medical testing. This, Rehm said, could influence insurance companies' willingness to cover whole-genome sequencing. That working group is currently pulling together data from the MGI's clinical labs to answer that question.

"To support the adoption of genome sequencing as a comprehensive clinical service — I would say that's our key goal," Rehm said.