Drs. Chong and Miller '(The paper) summarizes our perspective on the state of the field and the emerging technologies we think are most likely to be brought be to bear in the next decade.' Dr. Jessica Chong
National Scientific Consortium, with BBI Members, Exploring Tests to Discover Causes of Unexplained Genetic Disorders
‘Navigating the diagnostic odyssey is difficult for families’
A consortium of scientists at five leading research centers in the United States will soon publish a paper seeking to address a daunting challenge in precision medicine: identifying the best genetic test to make precise genetic diagnoses in families with a Mendelian condition.
One of those five centers is at the University of Washington and its researchers include several members of the Brotman Baty Institute. The GREGoR Consortium (Genomics Research to Elucidate the Genetics of Rare diseases), established in 2021 and funded by the National Human Genome Research Institute, seeks to develop and apply novel strategies to discover the basis of unexplained rare genetic disorders.
“The GREGoR Consortium has several precision medicine-related goals, but all of us are interested in how to improve diagnostic yield and gene discovery for genetic disorders,” said BBI’s Dr. Jessica Chong, an assistant professor in the UW Division of Genetic Medicine.
That interest has led to a paper, “Beyond the Exome: What’s next in Diagnostic Testing for Mendelian Conditions,” to which Chong and other BBI members of the consortium – Drs. Michael Bamshad, Danny Miller, Lea Starita, and Evan Eichler – contributed.
“This is a paper looking toward the future,” Chong said. “It summarizes our perspective on the state of the field and the emerging technologies we think are most likely to be brought be to bear in the next decade.”
The “state of the field” is as complex as it is complicated.
“Despite advances in clinical genetic testing, including the introduction of exome sequencing, more than 50 percent of individuals with a suspected Mendelian condition lack a precise molecular diagnosis,” the authors write. “Whole genome sequencing is increasingly clinically available, and newer technologies such as RNA sequencing, optical genome mapping, and long-read genome sequencing are emerging.” But, they note, “there is no clear guidance on the next best steps after inconclusive evaluation.”
The paper indicates there are several factors to the “varied and overall modest diagnostic rate” for patients undergoing clinical testing. Those factors include:
- The genetic basis of many Mendelian conditions remains unknown.
- The patient’s genetic test may not interrogate the appropriate gene, or variant type(s).
- Technical limitations may make it difficult to identify a pathogenic variant.
- The presence of variants of unknown significance, a situation exacerbated by different interpretations of variants by diagnostic laboratories.
In addition to challenges facing researchers and clinicians, the authors also are cognizant of the effects on patients and their families.
“Limited options for genome-wide testing exist for individuals who remain without a precise genetic diagnosis after current clinical testing options have been exhausted,” according to the paper, which is expected to be published in later this year in the American Journal of Human Genetics. “However, the value of these technologies over current testing strategies has yet to be determined across multiple clinical contexts and settings.”
BBI’s Miller reiterates the imperative to keep patients and families – and the inequities they face – foremost in researchers’ minds.
“Navigating the diagnostic odyssey is difficult for families, and probably favors families who have more resources, are native English speaking, and more likely to be White,” Miller said. “My hope is that this technology lowers those barriers for everyone. Long-read RNA sequencing will help us identify and understand variants that we might find with DNA sequencing, but have a hard time interpreting. I am really looking forward to a day when we’re doing paired DNA and RNA sequencing to finally provide comprehensive answers for individuals and their families.”
Miller and his lab provide both targeted and whole genome long read sequencing on the Oxford Nanopore platform to assist other researchers with their projects. Whether long read sequencing of DNA or RNA, or some other procedure, discovering the “best genetic test” will require more study and may take years to identify.
“We outlined considerations to keep in mind when deciding which emerging technology might be most useful, but the field is only beginning to study their applications,” Chong said. “I expect there will be surprises in store. Answering this question will be a priority for the field for some years to come.”