Boston Children’s Hospital has embarked on a strategic initiative to accelerate and expand its research genomics gateway, with plans to sequence the DNA of 3,000 patients with epilepsy or inflammatory bowel disease and their family members. Patients will have access to enroll in this pilot study if their condition is of likely genetic origin but lack a diagnosis after initial clinical genetic testing.
Sequencing will cover the entire exome, containing all of a person’s protein-coding genes. The Epilepsy and IBD were chosen for the pilot because Ann Poduri, MD, MPH and Scott Snapper, MD, PhD, have already made huge inroads into the genetics of these respective disorders. Both have built large, well characterized patient databases for research purposes, have disease-specific genetic expertise and have begun using their findings to inform their patients’ care. …
Anti-seizure drugs don’t work in about a third of people with epilepsy. But for people with focal epilepsy, whose seizures originate in a discrete area of the brain, surgery is sometimes an option. The diseased brain tissue that’s removed also offers a rare opportunity to discover epilepsy-related genes.
Many mutations causing epilepsy have been discovered by testing DNA taken from the blood. But it’s becoming clear that not all epilepsy mutations show up on blood tests. So-called somatic mutations can arise directly in tissues like the brain during early prenatal development. Even within the brain, these mutations may affect only a fraction of the cells — those descended from the original mutated cell. This can create a “mosaic” pattern, with affected and unaffected cells sometimes intermingling.
One of the first such mutations to be described, by Ann Poduri, MD, MPH, and colleagues at Boston Children’s Hospital in 2012, was in Dante, a young boy who was having relentless daily seizures. The entire right side of Dante’s brain was malformed and enlarged, and he underwent a drastic operation, hemispherectomy, to remove it. Only later, studying brain samples from Dante and similar children, did Poduri find the genetic cause: a mutation in the gene AKT3. It affected only about a third of Dante’s brain cells. …
Dante Bergskaug started seizing soon after he was born. He had a rare condition called hemimegalencephaly—the entire right side of his brain was enlarged and malformed. He had unusually severe epilepsy, and his doctors gave him a grim prognosis, telling his parents he probably wouldn’t live to the age of 2.
Peter Black, MD, then chief of Neurosurgery at Boston Children’s Hospital, thought otherwise. “He said, ‘I see him running around outside your house, playing ball with you,’” recalls Dante’s mother Gina.
In 2003, at just 5 months of age, Dante had a hemispherectomy, or complete removal of the abnormal half of his brain. There was little to be found about the operation on the Internet, and the few families with hemimegalencephaly that the Bergskaugs knew had refused surgery. But the decision wasn’t a hard one to make.
“Every day he would have 300 seizures,” Gina says. “The medications would fail one after another. He was hardly able to eat, was really not living the life you’d want for your child. If there was any hope to put an end to this, then we were going do it.”
Dante’s seizures dropped off sharply after the operation. The Bergskaugs donated some of his brain tissue to research, and from time to time met with a young epileptologist and research fellow, Annapurna Poduri, MD, MPH, who was doing genetic studies on the tissue and had lots of questions. …