Innovative approaches to genetic causes of unsolved Mendelian conditions

July 21, 2021

UW Medicine in Seattle will be part of a new National Institutes of Health effort to deploy innovative methods and approaches to find the genetic causes of unsolved Mendelian conditions.  These conditions are suspected of being the result of mutations in genes or other genomic differences – that have not yet been discovered.

More than 400 million people worldwide have been diagnosed with one of about 7,000 Mendelian conditions. Just a few examples of Mendelian conditions in which the genetic basis has already been determined are cystic fibrosis, sickle cell anemia, hemophilia, muscular dystrophy, color blindness, and Tay Sachs disease. But there are many more disorders for which answering questions for patients, families, and their clinicians still requires discovery of the underlying gene. 

According to today’s National Human Genome Research Institute announcement, the goal of the new consortium, composed of five institutions, will be to increase the number of Mendelian conditions whose genetic cause is known.

“Millions of people are born with rare diseases with unknown causes. Rare diseases are impactful in terms of the overall health of an individual,” said Deborah A. Nickerson, Professor of Genome Sciences at the University of Washington School of Medicine, a Researcher at the Brotman Baty Institute for Precision Medicine in Seattle and a Principal Investigator on the new grant.  “Currently, we can identify a mutation in only about 50% of persons with a rare disease. The new Mendelian Genomic Research Centers are going to develop new approaches to increase our ability to identify the causes of rare conditions.”

At least 3,000 Mendelian conditions are awaiting discovery of their genetic basis. Hundreds more new conditions of this nature are reported each year.

In earlier work with the NHGRI and in partnership with 685 institutions in 55 countries, the UW Medicine Mendelian genomics research team already has helped genetically test more than 15,000 samples from 5,675 families. The collaboration found genes for 1,379 conditions, including 915 novel finding. These results have provided immediate, substantial benefits for diagnostics and clinical care.

The Department of Genome Sciences at the UW School of Medicine was also among the leaders in examining only the coding parts of the human genome, called the exome, to find genetic characteristics behind some Mendelian conditions, such as Kabuki syndrome and Miller syndrome. The genes underlying these syndromes had been impossible to determine through previous approaches.

The scientists also have made headway in understanding the role of parts of the genome that don’t code for proteins.  While causative variants are most likely to lie in protein-coding regions, non-coding areas might also hold clues to the origins of some Mendelian conditions. Some of these non-coding regions of the genome have regulatory or other functions that manage how, for example, certain areas of DNA are turned on or off, how much and when proteins are produced, or when parts of the DNA are opened or closed for reading of the code by RNA. 

The University of Washington Mendelian genomics research team has also established ways for families to assist with research by exchanging data with clinicians and genome researchers through a website called, as well as through a public data browser in which their personal identifiers are removed.

Under this latest national consortium, the UW Medicine Mendelian genomics team will use next-generation sequencing, new paradigms, and advanced sequencing technologies to help efficiently uncover novel genes for as many Mendelian conditions as possible.

The researchers also plan to work on new strategies for finding variants that are difficult to detect, or that have unknown functional effects or unusual patterns of inheritance in families. They will be checking, for instance, for structural variants in the genome, repeat expansions, and cryptic splice variants. They will conduct follow-up studies to characterize the architecture of variants in non-coding genome regions that have a potential link to disease, and to ascertain their pathogenic role. 

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