NHGRI Takes New, WGS Look at Mendelian Diseases

By Allison Proffitt

July 27, 2021 | The National Institutes of Health has made a five-year, nearly $80 million commitment to the establishment of a  Mendelian Genomics Research Consortium of five clinical laboratories and one data coordinating center. The Consortium will build on previous National Human Genome Research Institute (NHGRI) work to develop new methods for identifying the genetic causes of single-gene diseases.

The clinical centers will be run by Stephen B. Montgomery, Ph.D., at Stanford University School of Medicine, Stanford, California; Deborah A. Nickerson, Ph.D., at the University of Washington, Department of Genome Sciences, Seattle; Anne O'Donnell-Luria, M.D., Ph.D., at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and Boston Children's Hospital; Eric J. Vilain, M.D., Ph.D., at the Center for Genetic Medicine Research at Children's National Hospital, Washington, D.C.; and Jennifer E. Posey., Ph.D., at the Baylor College of Medicine, Houston. The data coordination center, run by Susanne May, Ph.D., at the University of Washington School of Public Health, Seattle, will manage the release of genomic data and facilitate data sharing. 

Over 400 million people worldwide have been diagnosed with Mendelian diseases, or diseases we believe to be linked to a single gene. And NHGRI has been actively working to uncover the genetic bases of these diseases through the Centers for Mendelian Genomics, primarily using whole exome sequencing (WES). 

“This program was quite successful in achieving this, and more importantly, in enabling other labs to use WES to do it too,” Lisa Chadwick, Program Director, Genome Sciences, Division of Genome Sciences at NHGRI, told Bio-IT World. But the finish line seems to be receding, she explained. 

There are about 7,000 known Mendelian diseases today, and the underlying gene has been identified for 67% of currently known Mendelian phenotypes. However about 200 new Mendelian phenotypes are being delineated every year even as researchers find causal genes for about 300 diseases each year. “Even though it seems like we are getting close to solving all of the Mendelian diseases, the finish line keeps moving!” she said.

The biggest challenge for the new consortium will be approaching the >50% of cases that haven't been solved thus far using WES, and that will mean employing new strategies.

“WES is cost-effective and can be quite informative in many cases,” Chadwick explained. “WES will likely remain a first-line approach for genomic studies of Mendelian Diseases. However, WES has limitations that impact the kinds of mutations that it is able to detect.” WES, limited to the exome, does not generally handle structural variants or copy number variants well. 

So the new consortium will focus on using other approaches like whole genome sequencing (WGS), RNA-seq, and other molecule assays. “One challenge of doing WGS is that you're now looking in a much, much larger space, and researchers are still working on identifying and annotating the functional elements in the genome,” Chadwick said. “To help with this, we will also be working on new ways to prioritize candidate variants that occur outside of coding regions, and to test their functional impact in a high-throughput way.” 

Deliberate Data Approach 

The Consortium is also focused on new analytical approaches to the data and improving data sharing and collaboration. As with any rare disease, understanding Mendelian disease genetics can be greatly aided by considering other patients with the same disease. But those patients can be hard to find. 

“Because data sharing is so important, we funded a data coordination center as part of this program,” Chadwick said. “They will help us make our data as broadly accessible as possible so that we can make these important connections with other researchers, and they will try to develop new ways for researchers with unsolved cases to connect with each other.” 

The Consortium is also tackling a more fundamental question: are these Mendelian diseases truly tied to single genes? Some of the trickier ones, probably are not, Chadwick said. 

“There may be one major gene, but there might also be other mutations in other genes that also contribute to the phenotype in a significant way (oligogenic). Sometimes the phenotypes can be changed by these other genes in ways that make it hard to tell whether they are the same disease or two different diseases. You really need comprehensive phenotyping data to be able to sort this out, and that is not always available, or may not have been collected in a way that makes it easy to compare to other patients,” she said.

The data coordination center plans to help standardize the collection and sharing of phenotype data to build a better foundation for comparing diseases. 

“By examining several approaches, developing standards, and encouraging sharing of data and methods, this consortium will be well positioned to determine whether there are distinctions within the pool of single-gene diseases that can be approached in specific ways (vs using a similar multi-pronged approach for all diseases).”