For a long time, said Matthew W. State, M.D., FW ’00, Ph.D. ’01, he couldn’t explain to parents why their autistic children lacked social awareness, or offer them treatment effective in ameliorating the core symptoms of the syndrome. Almost nothing was known about the biology of the disease. But thanks to advances in genomic technologies, including sequencing—the cost of DNA sequencing dropped from $100,000 in 1998 for a million base pairs to $0.07 today—studying rare genetic variation is now relatively fast and economical. As co-director of the Yale Neurogenetics Program, State works with fellow co-director Murat Günel, M.D., who uses the technology to identify genetic variation in individuals with brain malformations. Together, they try to discover the genes behind psychiatric and developmental disorders.
The two discussed this unusual collaboration between a psychiatrist and a neurosurgeon at the alumni reunion’s Saturday morning scientific session.
State started with the basics: any two people are roughly 99 percent genetically identical, but gene discovery efforts focus on that 1 percent of difference. There are, he explained, different types of genetic variation: for example, germline, which is inherited, and spontaneous or de novo variation, which occurs at the moment of conception in sperm or egg cells.
In his search for genetic variants linked to autism, State is studying families he described as hit by a “genetic lightning bolt”—couples who have no errant genes linked to autism yet have an autistic child. State’s team sought variations that appear in the child but not in the parents. He looked for copy number variants (CNVs), additions or subtractions of bits of DNA, and found an overrepresentation of CNVs in autistic individuals. Such mutations were found to increase the risk of autism 5- to 16-fold. His team also found a region of the genome consisting of 25 genes that cause the hypersocial disorder known as Williams syndrome when these genes are missing but cause autism when they are duplicated.
But CNVs can be thousands of base pairs long and include multiple genes, making it tough to pinpoint the specific factors connected to a disease. So State’s team used exome sequencing to focus only on protein-encoding portions of the genome and identified three genes of interest. Three other papers published at the same time confirmed their findings and added another three new autism genes to the list. State’s experiments show how far understanding of autism has come—from mainly speculation to replicable genetic findings that may lead to novel treatments.
State also discussed his work on Tourette syndrome, a disorder characterized by chronic vocal and motor tics, found in 0.3 to 1 percent of the population. In 2010, State studied a family in which a father and eight children had Tourette syndrome. The mother was not affected. State found that the father and children shared a mutation that disrupted the function of a protein connected with histamine—a neurotransmitter involved in memory, feeding, weight, cognition, and other pathways. Histamine serves to balance dopamine, another neurotransmitter involved in reward pathways; the researchers suspected that the disruption of histamine leads to dysregulation of dopamine. These findings offer insights into biology that can be targeted by known medications, offering novel ways of thinking about treatment
Co-director Günel discussed advances in sequencing technology that are helping to elucidate developmental and vascular disorders of the brain, focusing on aneurysms. Günel has used exome sequencing to identify genetic variation in individuals with brain malformations and has pinpointed three areas of the genome that are responsible for a spectrum of brain malformations.
Exome sequencing can also be applied to such common disorders as hypertension, diabetes, cancer, and brain aneurysms, providing insight into the pathophysiology of disease when traditional genetic approaches have failed, Günel explained. Assessing genetic risk of brain aneurysms, he said, will be a particular benefit of this technology, as aneurysms are responsible for a quarter of stroke mortality but have few warning signs.
But Günel acknowledged that genetics are only part of the story—there are also environmental factors that influence a person’s risk of developing these brain disorders. But Günel and State’s study of specific genetic contributions has already shed much light on formerly mysterious disorders and is showing the way to novel treatments.
“There’s never been a more exciting time to be in the game,” State said.