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New effort to discover genetic causes of single-gene disorders

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Extreme close up genome
Photo courtesy of National Human Genome Research Institute

The University of Washington Genetics Analysis Center (GAC), based in the School of Public Health’s Department of Biostatistics, will serve as the Data Coordination Center (DCC) for a new Mendelian Genomics Research Consortium. Funded by the National Human Genome Research Institute (NHGRI) within the National Institutes of Health (NIH), the consortium seeks to significantly increase the number of known single-gene disorders.

 

"This consortium goes a significant step beyond NHGRI’s already successful efforts in this area, but adds a more intense focus on data sharing and enabling the broader research community to tackle challenging diseases whose genetic causes were eluding identification by researchers,” said Carolyn Hutter (MS ’09 Biostat, PhD ’08 Epi), director of the NHGRI Division of Genome Sciences.

 “The World Health Organization estimates over 10,000 diseases to be single-gene or ‘monogenic.’ Some examples of single-gene disorders are cystic fibrosis, sickle cell anemia, and Huntington’s disease. While each individual disease may be rare, they are all-together quite common in the global population,” said Susanne May, professor of biostatistics and contact PI for the DCC.

Katie Golden-Grant, genetic counselor in the UW School of Medicine’s Division of Medical Genetics, will lead program outreach and education for the DCC.

“For families affected by rare disease, identifying and understanding the underlying cause allows an accurate diagnosis to be made, prompting a customized care approach, and sometimes specific treatments,” said Golden-Grant.

“Identifying a precise diagnosis allows for an understanding of the pattern of inheritance in the family. A diagnosis can empower families to make informed choices regarding their medical care and family planning, prompt important conversations between relatives, and facilitate connection and support among families and individuals affected by the same condition.”

Golden-Grant notes that it currently takes an average of six to eight years for a person with a rare disease to be accurately diagnosed, and many remain undiagnosed for decades. “The more that we understand the role our genes play in health and disease, the shorter this diagnostic odyssey will be for families.”

On a broader scale, identifying the genes underlying Mendelian disorders helps researchers understand the function of these genes in everyone. Even though the human genome was mapped more than 20 years ago, there are still many genes whose function or importance are yet to be discovered.

“Though gene therapy and other precision medicine therapeutics are very promising, they require a thorough understanding of the molecular cause and mechanism of disease. A better understanding of the genetic contributors to rare disease will pave the way for expansion of treatment options for affected individuals,” said Bruce Weir, professor of biostatistics and multiple PI for the DCC.

Recently, researchers have been identifying about 300 Mendelian disease genes each year using a technique called whole-exome sequencing. This method sequences all the regions of the genome responsible for encoding proteins. However, whole-exome sequencing has not been successful in identifying the genes responsible for many Mendelian diseases, requiring new ways of approaching the problem. To achieve this, consortium investigators will engage in enhanced data sharing and collaboration, and focus on applying new technologies, genome sequencing strategies and analytical approaches.

GAC understands how to successfully lead the scientific and administrative facets of MGRC, having served as the coordinating center for several large-scale genomics research projects. GAC possesses expertise in biostatistics, statistical genetics, software and pipeline development, data management, science communication, and bioethics.

“We are excited to be delving into a new area of genetic research for our center - the study of Mendelian conditions. Most of our prior coordinating center work has been in the study of common, complex disease in population-based studies - which is very distinct from understanding the genetic causes of rare, single-gene disorders in patients and families,” said Sarah Nelson, GAC research scientist and scientific contact in the DCC’s project management team.

“There are also some new types of molecular data we are excited to work with - beyond genome sequencing data - which will be utilized to help determine the underlying cause of thus-far unsolved Mendelian conditions. However, there are commonalities in providing scientific and administrative support in the service of cross-site collaboration and analysis and supporting data sharing with the broader scientific community.”

Initially, GAC will connect with consortium research centers to better understand the types of data each works with, their areas of expertise, etc. It will also build an operational framework that includes communication channels, collaboration processes, and training on a new data sharing and analysis platform.

In addition, GAC plans to engage with the public, families affected by rare disease, clinicians, and researchers through various forms of outreach.

“We want to be sure that clinicians caring for individuals with rare disease are aware of the consortium sites as a resource for their patients. We also plan to partner with advocacy groups to spread awareness of the work and aims of the participating sites and seek to understand the barriers to research participation among individuals with rare disease. It is a goal of our team to educate and engage the public in our work in order to raise awareness of rare diseases and improve understanding of the utility of data sharing and genetics research more broadly,” said Golden-Grant.

 - Deb Nelson, UW Biostatistics Communications