Hard-to-detect chromosomal anomalies explain neurodevelopmental birth defects

BCAs are changes to the structure of an individual's chromosomes, in which one or more fragments of DNA breaks apart from the regions around it and is reattached elsewhere in the genome, either on the same chromosome or a different one. In their simplest form, a single fragment is moved to another region of the genome, but more complex BCAs may involve more than one fragment from more than one chromosome.

Unlike chromosomal deletions or duplications, BCAs do not result in the gain or loss of any genetic material. However, they do disrupt the function of DNA at the breakpoints of the fragments involved, in both their original locations and their new ones, and have been implicated in neurodevelopmental birth defects.

"We studied BCAs in 111 patients with congenital neurodevelopmental conditions and 36 with other conditions and mapped where the breakpoints were," explained Claire Redin, PhD, a postdoctoral researcher at Massachusetts General Hospital and the Broad Institute, and first author on the new study. "By mapping the breakpoints, we were able to identify genes that were disrupted in patients with birth defects, which suggests that these genes play a key role in normal brain development," she said.

Because no genetic material is gained or lost, conventional tools for genome analysis cannot generally detect BCAs. Thus, they have not received much attention as a significant cause of disease. To overcome this challenge, Dr. Redin and her colleagues used a modified version of whole-genome sequencing that utilized large, overlapping strands of DNA to find the breakpoints. When sequences that are normally located far apart in the genome were found on the same strand or adjacent ones, the researchers were able to confirm that a BCA had brought them together and look more closely to identify the genes disrupted at the breakpoint.

"As a first step, we looked at how the breakpoint locations mapped relative to known disease genes, to see how many of the defects we observed in patients could be explained by disruptions to these," Dr. Redin said. They found that 46 percent of breakpoints disrupted a single gene; 24 percent disrupted regions between genes; and 30 percent disrupted at least two genes.

The researchers also studied other genomic features near the breakpoints to see what may be triggering the DNA to break apart at that location. Somewhat unsurprisingly, they observed that breakpoints tended to coincide with known recombination 'hotspots' -- specific regions where genetic exchange between a person's corresponding chromosomes tends to occur. They also identified genomic regions where BCAs seemed to cluster, including one narrow band in a region between genes, in which nine patients with similar neurodevelopmental conditions showed a breakpoint.

"There is obviously something unusual happening where the BCAs clustered, which we plan to study in future work," Dr. Redin said. The researchers are currently conducting a more detailed analysis of the 24 percent of breakpoints located between genes and how these may affect brain development.

"Our eventual goal is to be able to predict the effects of BCAs based on where they are located and which genes are disrupted," Dr. Redin said. "The data we collect through this study and future ones will help us work toward this predictive model."