The discovery of mutations in genes that help regulate brain growth could lead to better treatments for brain disorders and other conditions, including cancer, autism and epilepsy.

Inquiry Brain Growth Genes Dobyns 220x130

The 2012 discovery of mutations in genes that help regulate brain growth has moved geneticist Dr. William Dobyns closer to his lifelong goal of identifying the causes of developmental brain disorders in children. He led research associating new mutations in three genes (AKT3, PIK3R2 and PIK3CA) with large brain size (megalencephaly). These genes are also associated with many other conditions, including cancer, autism and epilepsy, hydrocephalus, birthmarks and other vascular anomalies, and overgrowth disorders such as Klippel-Trenaunay syndrome. Medications currently being developed to treat cancer could one day slow the increased and unregulated growth that occurs in these conditions, Dobyns says.

AKT3, PIK3R2 and PIK3CA are present in all humans, but specific changes or mutations in the genes that make them overactive lead to these conditions. PIK3CA is a known cancer-related gene that appears able to make cancer more aggressive. Findings related to AKT3 and a rare condition known as hemimegalencephaly were published in April 2012, and similar findings related to PIK3CA and a rare condition known as CLOVES syndrome appeared in May 2012.

The research team led by Dobyns discovered additional proof that a person’s genetic makeup is not completely determined at the moment of conception, but can change in significant ways in the days or weeks after conception. Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare.

I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children.” – Dr. Jim Olson

The findings could lead to new treatments for children in the next decade, predicts Dobyns. “This is a potentially very important finding. Not only does it provide new insight for certain brain malformations, but it also provides clues for what to look for in less severely affected children and adults including some relatively common conditions,” he says. “Kids with cancer, for example, do not usually have a brain malformation, but they may have subtle growth features that haven’t yet been identified. Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers.”

“This study represents ideal integration of clinical medicine and cutting-edge genomics,” says Dr. Jim Olson, a pediatric cancer expert at Seattle Children’s and Fred Hutchinson Cancer Research Center who was not affiliated with the study. “I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children. The team ‘knocked it out of the park’ by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway.” AKT3, PIK3R2 and PIK3CA all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the “culprit pathway” referenced by Olson.

Gene sequencing finds mutations

Researchers at Seattle Children’s Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children. “Based on what we’ve found, we believe that we can eventually reduce the burden of these disorders and the need for surgery for kids with hydrocephalus and some types of epilepsy, and change the way we treat other conditions,” says Dobyns.

The team’s discovery was made through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing. An exome is the most functionally relevant part of a genome and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism. Seattle Children’s Research Institute conducted this study in collaboration with teams from University of Washington Genome Sciences Department, FORGE (Finding of Rare Disease Genes) Canada Consortium, Cedars Sinai Medical Center and University of Sussex.