Gene, interrupted
By Martha McKenzie
All through high school and college, Jennifer Mullé remembers waking up each morning and thinking, "Is today the day I start hearing voices?"
One of Mullé's aunts had schizophrenia, and another had psychosis. "I would hear my parents talking about them. Long before I knew anything about genetics, I knew I was at risk," says Mullé, assistant professor of epidemiology at Rollins.
The knowledge that she was vulnerable to developing the disease that plagued her family shaped Mullé's young adulthood and career. Schizophrenia is a mental disorder characterized by delusions and/or hallucinations that leave sufferers unable to distinguish between what is real and what is not. It generally strikes young adults, with the risk for developing the disorder peaking between ages 20 and 25 and dropping off by age 30.
During her early to mid-20s, Mullé did little but wait for the onset. Although she attended college, she did not apply herself. She did not allow herself to become entwined with boyfriends. She did not plan a career.
"My future seemed so uncertain, I just couldn't commit to anything," she says.
But as she neared 30 with no signs of schizophrenia, she decided it was time to start her life in earnest. She had become interested in public health while volunteering at an emergency room during college. One night a baby was rushed in who appeared to have been thrown against a wall. Mullé watched as the neurosurgeons painstakingly removed a small section of the baby's skull to relieve the pressure.
"I remember thinking, 'These surgeons are doing this incredibly complex, lifesaving procedure, but what if the baby hadn't been thrown against the wall in the first place?' I decided that I wanted to be on that end of the equation," she says.
Mullé combined that interest in public health with her fascination in genetics and earned an MPH in genetic epidemiology. She went on to get a PhD in human genetics, and then turned her attention to discovering the genetic underpinnings of schizophrenia.
She soon found a clue. In a small collaborative study she was leading, Mullé noticed one participant was missing a set of genes from a particular chromosome. She was intrigued.
She scoured other schizophrenia studies. The 3q29 deletion turned out to be very rare—Mullé thinks it affects one in every 30,000 births, or about 2,000 people in the U.S. under the age of 18. But people who have it are 40 times more likely to develop schizophrenia than the general population. (The name 3q29 is sort of an approximate address for the deletion. The "3" stands for chromosome 3, the "q" is the long arm of chromosome 3, and 29 is the area on the chromosome where the genes are missing.)
"That's huge," says Mullé. "After we discovered that, I wanted to know everything I could about that region on the chromosome."
It turns out doctors had been diagnosing children with 3q29 deletion syndrome for some time. The deletion in children leads to mild to moderate intellectual disability and is associated with autism.
"This really complicated things for me, because these young children were getting diagnosed with 3q29 deletion, and I knew something about them that no one else did," says Mullé. "At that time, there were two published studies, which described a total of 15 patients in the world. That was the sum total of what we knew about the 3q29 deletion syndrome. Nobody had linked the deletion to schizophrenia yet, but now I knew these kids were at increased risk."
So Mullé created an online registry to provide information and support to the children and their families and to collect information to learn more about the rare syndrome. Now just over a year old, the 3q29 Deletion Registry (at 3q29deletion.org) has 48 members, and Mullé has already gleaned a wealth of information.
Most of the children in the registry were diagnosed before age 5. They all have some form of intellectual disability, and more than a quarter have autism. But the registry has revealed much more.
"The average age of the registry population is 11, so these are young kids. Yet already six have been diagnosed with an anxiety disorder," says Mullé. "We have depression and bipolar disorder. Almost a third have recurrent ear infections. One quarter have heart defects. And more than 70% had feeding problems as babies—some children ended up with feeding tubes for several years. I think it helps parents to know that other children with 3q29 deletion are having the same problems—they are not alone."
Judging by emails sent to Mullé by the families, it does help. Parents' messages include
• "No one seems to know about it… except perhaps you."
• "I would like to thank you for taking the time to do this study. It means a lot to our family."
• "My family feels so fortunate to have you on our team. The work and research you do is amazing, and we are most grateful to you for your efforts."
• "The clinic told us our child was the first case they had ever seen."
In an attempt to understand the underlying biology of the syndrome, Mullé is working with doctors at Emory School of Medicine's Department of Human Genetics to create a mouse model.
"I hope we learn how many people with this deletion are going to develop schizophrenia, and among those who do, if there is a particular treatment regimen that can be recommended," she says. "The 3q29 deletion is the biggest clue we have.
