December 12, 2011

Solving unknown causes of inherited diseases

$16 million grant launches four-year undertaking to identify genetic causes

The McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, in collaboration with Baylor College of Medicine, has been named one of three Mendelian Disorders Genome Centers by the National Human Genome Research Institute and will receive $16 million over the next four years to identify causes of genetic disease. The center will be called the Baylor-Hopkins Center for Mendelian Genomics. The other two centers will be at University of Washington and Yale University.

“Although they are individually rare, Mendelian disorders in aggregate account for more than 10 percent of inpatients in pediatric hospitals. Moreover, one-third or more of the patients we see in our genetics clinic who clearly have inherited conditions remain undiagnosed after exhausting all possible and available tests,” said David Valle, the Henry J. Knott Director of the McKusick-Nathans Institute of Genetic Medicine. “Now we have the opportunity to solve many of these unknown diseases by identifying the genes and genetic alterations associated with them.”

Valle will co-direct the new center with his counterpart at Baylor, James Lupski.

An estimated 25 million Americans suffer from inherited diseases, most of which are considered rare, afflicting fewer than 200,000 people each. So-called Mendelian disorders are caused by a change in a single gene and are inherited in a manner first observed in the 19th century by Gregor Mendel, an Austrian monk. Many of the 5,000 known Mendelian disorders, such as cystic fibrosis and muscular dystrophy, are well-known, but many more are so rare that they affect only a few dozen families.

Johns Hopkins manages and curates OMIM, the Online Mendelian Inheritance of Man, an encyclopedia of known genetic conditions; how they manifest; and the genes, if known, that contribute to them. OMIM currently contains 3,000 unexplained Mendelian conditions.

Previously, the challenges to identifying the single genetic cause included the need to assemble many large families, which is time-consuming, labor-intensive, costly and difficult because of the rarity of individual disorders. “But now, due to what we’ve learned from the Human Genome Project, the rapid evolution of sequencing technology and the power of genetics, we’re at an exciting time where we can solve many of these diseases in just a few months, using samples from a small number of affected individuals and their families,” Valle said. “This new grant enables us to assemble the team and perform the studies needed to accomplish this task.”

The three centers will collaborate with a worldwide network of rare-disease experts to gather samples from thousands of people with these conditions and sequence their genomes to identify the genetic variants responsible for the disorders. To collect new patient samples, the Johns Hopkins–Baylor group hopes to capitalize on its global network of former trainees to identify patients and families with unknown inherited conditions and send DNA samples for sequencing. Valle says that they are interested in families afflicted with recognizable conditions for which the culprit gene is unknown, families afflicted with conditions for which genes are known for some small population of patients but are not altered in these families, and families afflicted with inherited conditions that thus far remain undiagnosed.

“We expect that the knowledge about genetic variants that underlie Mendelian disorders will facilitate rapid and accurate diagnosis and might lead to new therapeutic approaches,” said Lu Wang, National Human Genome Research Institute program director for the Mendelian Disorders Genome Centers Program. “This knowledge can also shed light on more common, complex diseases that involve similar genes, pathways and phenotypes, and contribute to the understanding of basic human genetics.”

To jump-start these projects, the centers already have solicited thousands of samples from researchers studying several hundred rare disorders. The centers will continue to solicit samples and maintain a public list of available materials. The University of Washington will serve as the coordinating center for the program. The centers plan to join the International Rare Disease Research Consortium, whose goal is to develop diagnoses of most rare diseases and treatments for about 200 disorders by 2020.

“In addition to solving Mendelian disorders, we hope to learn more about the general principles of disease and understand disease mechanisms at a much deeper level,” Valle said. “We’re excited about what this can teach us and how we hope to use this information to improve the outcomes for patients and families with these rare disorders.”


Related website

McKusick-Nathans Institute  of Genetic Medicine at  Johns Hopkins