While some diseases stem from a web of influences including environment, lifestyle choices, and genetic luck, others result from a single mutant gene. While the inheritance patterns of these so-called Mendelian disorders are straightforward, finding the errant genes is not.

More than 6,000 rare Mendelian disorders have been identified in the United States. Collectively, they afflict more than 25 million people, but each affects fewer than 200,000 people. The fewer patients who have a disease, the harder it is to study, because both funding and genetic samples are limited—yet discerning their genetic causes may lead to treatments and yield broader insights into human biology.

“There are roughly 22,000 genes in the human genome,” said Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and a principal investigator of a new grant from the National Institutes of Health. “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 four-year $11.2 million grant has established the Yale Center for Mendelian Genomics, to be located on the West Campus. The grant, announced in December, will fund two other centers devoted to Mendelian diseases—one at the University of Washington in Seattle and one operated jointly by Baylor College of Medicine in Houston and the Johns Hopkins University in Baltimore.

At Yale, principal investigators include Murat Günel, M.D., HS ’98, the Nixdorff-German Professor of Neurosurgery and professor of genetics and of neurobiology; Shrikant Mane, Ph.D., senior research scientist in genetics; and Mark B. Gerstein, Ph.D., the Albert L. Williams Professor of Biomedical Informatics and co-director of the Yale Computational Biology and Bioinformatics Program.

Underlying the new project is exome sequencing, a gene sequencing method that targets those parts of the genome that encode proteins. Many 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. This has really opened up the field,” said Lifton, a Howard Hughes Medical Institute investigator.

The new center hopes to identify patients with these mutations and learn the consequences of each genetic deviation. “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,” said Lifton.

The Yale team also expects to learn some lessons in basic biology. The link between each gene mutation and disease can teach scientists a great deal about what happens when those same genes function normally, Lifton said. “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.”