Center will study rare genetic diseases

For complex diseases like cancer and diabetes, there’s no crystal ball that can tell you for sure whether you’ll develop the illness during your lifetime. A tangled interplay between your environment, your behaviors, and the genes you inherited from your parents determines your risk of such diseases. But for some disorders—dubbed Mendelian—a mutation in a single gene is the direct and clear-cut cause of disease. And the inheritance patterns of Mendelian disorders are also straightforward, but discovering the genes responsible for these inherited diseases is not always easy.

More than 6,000 rare Mendelian disorders (defined by Congress as disorders affecting fewer than 200,000 Americans) have been identified. Some, such as cystic fibrosis, are well-known, but many others affect only a handful of individuals. The fewer patients with a disease, the harder it is to study, because of limited funding and limited genetic samples to compare, and scientists have so far found the genetic cause of only about half of the known Mendelian disorders. But all together, these rare diseases afflict 25 million individuals in the U.S., and uncovering their genetic causes could not only lead to treatments for these disorders, but would bring broader insights into human biology that may aid our understanding of common diseases. For example, by studying familial hypercholesterolemia, a Mendelian disorder causing very high cholesterol levels, scientists have developed new ways to treat more common causes of high cholesterol.

Now, a four-year, $11.2 million grant from the National Institutes of Health has established the Center for Mendelian Genomics at Yale (CMGY), providing researchers with the resources to tackle the genetics of these rare disorders.

“There are roughly 22,000 genes in the human genome,” says Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, one of the principal investigators of the new grant. “Right now we know what diseases result when about 3,000 of those are mutated. We know almost nothing about what happens when the remaining ones are mutated.”

The new grant, announced last December, will also fund two other national centers devoted to the genetics of Mendelian diseases—one at the University of Washington, in Seattle, Wash., and one operated jointly by Baylor College of Medicine, in Houston, Texas, and at Johns Hopkins University, in Baltimore, Md.

“Between all the institutions, we collectively want to solve all of the remaining Mendelian diseases,” says Lifton, also a Howard Hughes Medical Institute investigator. “And we’ll be working as a consortium. So each group has its own strengths in particular clinical areas, and the goal is to minimize any overlap of work that’s done.” Genetic samples submitted from clinicians through a single Web portal, Lifton explains, will be distributed to the three centers based on their interests.

At Yale, other principal investigators at the new center will include Murat Günel, M.D., the Nixdorff-German Professor of Neurosurgery and professor of genetics and neurobiology; Shrikant Mane, Ph.D., senior research scientist in genetics; and Mark B. Gerstein, Ph.D., the Albert L. Williams Professor of Molecular Biophysics and Biochemistry and co-director of the Yale Computational Biology and Informatics Program.

Over the last decade, Yale has spearheaded the development of exome sequencing, the gene sequencing method that the new project relies on. Rather than spell out every nucleotide in the human genome, as genomic studies have traditionally done, exome sequencing allows researchers to focus only on those parts of the genome that encode proteins, the physical machinery of cells. A large fraction of inherited diseases are thought to be due to mutations in the exome.

“The new sequencing technologies enable us to pinpoint disease-causing genes even with only a few affected subjects,” says Lifton. “This has really opened up the field.” (See “The bench-top revolution.”)

There is already a network of clinicians around the world who refer patients with rare diseases to School of Medicine researchers for genetic and other testing, follow-up, and possible treatment. Lifton and his colleagues have focused especially on connections with doctors in the Middle East, where culturally sanctioned marriages between cousins lead to a higher rate of rare genetic disorders than is seen in the U.S. “With 7 billion people on the planet, even the rarest mutations are present and walking around somewhere,” says Lifton. It’s the goal of the CMGY to identify patients with all these rare mutations and learn the consequences of each genetic deviation. In the process, they may also learn how to treat some patients.

“Identifying the specific genetic causes of these diseases will be useful diagnostically; the therapeutic possibilities will only be revealed when we can link mutations to disease traits,” Lifton says. But he anticipates that by discovering the genetic causes of some of the disorders, doctors will be able to develop better ways to treat them. “If you look at the most promising targets in the pharmaceutical industry today, almost all of them arose from the recognition of what happens when genes are mutated in humans.”

And beyond the therapeutic implications of the new project, the Yale team expects to learn some lessons in basic biology. The link between a given gene mutation and the disease it causes can teach scientists a great deal about what function that same gene performs normally, Lifton explains. “It really tells us how each gene works in the context of the human body. And this tells us a great deal about how entire pathways work, which is very important to future drug development.”