The Y chromosome could help point the way to new answers about the neural mechanisms of autism spectrum disorder (ASD). Studies underway at The Children’s Hospital of Philadelphia are seeking possible structural and functional differences in the brain associated with having an extra copy of this male sex chromosome, a condition known as 47,XYY syndrome. Typically, human males have one X and one Y sex chromosome, while the remaining 22 pairs of chromosomes do not vary by sex.
“This seems like an interesting way of probing the neural correlates of the Y chromosome,” said study co-leader Timothy Roberts, PhD, vice chair of research in Radiology at CHOP and a professor of Radiology at the Perelman School of Medicine at the University of Pennsylvania.
Boys with 47,XYY syndrome generally are physically healthy, but they are sometimes larger in physical size, and are more likely to experience delays in learning and physical development, as well as various behavioral problems. And, Dr. Roberts’ collaborator and study co-leader Judith Ross, MD, a professor at Thomas Jefferson University, has observed one other important difference: Boys with this condition are far more likely than the general population to meet diagnostic criteria for ASD, at a rate of about one in four, compared to one in 68.
“Once we were aware of that, we started thinking of XYY as a human genetic model of autism,” Dr. Roberts said. He added that it was a particularly attractive genetic model because boys are overall four times more likely to be diagnosed with ASD than girls, which could imply a role for genes on the Y chromosome as a contributor to many other cases of ASD. And studies comparing the presence vs. absence of an extra Y chromosome between boys with and without 47,XYY syndrome would introduce fewer variables than comparing the presence of a Y chromosome in boys to the presence of a second X chromosome in girls.
The National Institute of Mental Health of the National Institutes of Health recently awarded Dr. Roberts and Dr. Ross a new grant to examine neural measures of boys with 47,XYY syndrome, focusing on structural and functional markers in the brain that have been identified as differing between children on the autism spectrum and typically developing children. They are using magnetic resonance imaging and magnetoencephalography to measure these biomarkers.
By pairing this newly funded study group with related research already underway with funding from the Department of Defense (DoD), the team will address larger questions and perform more complex comparisons to better understand the neural differences associated with meeting ASD diagnostic criteria and those associated with the Y chromosome, in various combinations.
Participants in the DoD-funded arm of the study include three age-matched groups: boys with 47,XYY syndrome, boys who do not have 47,XYY syndrome but are on the autism spectrum, and typically developing boys.
The first question the researchers want to address is whether ASD looks the same or different in the brain, depending on whether boys have one Y chromosome or two. If ASD is more homogeneous in the 47,XYY population, then any signature neural features in this population could point to new findings about the genetic contribution of the Y chromosome to neural structure or function.
Another critical question: If an extra Y chromosome increases the likelihood of ASD compared to the general population, why does it only raise that chance to one in four? Dr. Roberts and Dr. Ross are interested in finding any neural differences in the three out of four boys with 47,XYY syndrome who do not meet ASD diagnostic criteria. Those differences might provide insight into mechanisms of ASD or into pathways to target for interventions.
“It’s likely that through this work we will find something helpful to families and boys with XYY,” Dr. Roberts said. “I hope some mechanistic findings will be generalizable to the broader ASD population. And I hope even more that we’ll identify something protective or compensatory in the nonsymptomatic boys with XYY that can then be generalized to help the ASD population at large.”