NEW YORK – New research suggests that a subset of focal epilepsy cases can be traced back to mosaic mutations in the brain that result from copy number alterations arising on the 1q arm of chromosome 1 during maternal meiosis. Those mutations are repaired post-zygotically in other tissue types — in contrast with somatic mosaic mutations that occur at a post-zygotic stage of fetal development.
"Our findings represent a novel mechanism through which brain mosaicism arises in development," co-senior and co-corresponding authors Tracy Bedrosian, a researcher affiliated with Nationwide Children's Hospital and Ohio State University, and Erin Heinzen, an investigator at the University of North Carolina at Chapel Hill, and their colleagues wrote in Nature Genetics on Monday.
Starting with a group of 196 individuals with focal epilepsy and brain malformations, the researchers focused in on half a dozen pediatric patients between the ages of 2 and 7 months with mosaic chromosome 1q gains and a shared set of symptoms such as infantile spasms, early-onset epilepsy, neurodevelopmental delays, and cortical dysplasia.
"Resected tissue from all six patients showed evidence of cortical malformation and hyaline astrocyte inclusions in the cortex — a relatively rare neuropathological feature previously reported in a subset of patients with epilepsy, but for which no genetic etiology has been determined," the authors explained.
With a combination of exome sequencing on brain and blood samples, fluorescence in situ hybridization, and single-cell whole-genome sequencing, the researchers searched for mosaic mutations in these six cases, alongside exome sequences for 342 controls from the North American Brain Expression Consortium and whole-genome sequences for 15 controls from the National Institute of Mental Health Data Archive's Brain Somatic Mosaicism Network.
The team's subsequent structural analyses — which included optical genome mapping or long-read sequencing on brain tissue samples for two focal epilepsy patients with chromosome 1q tetrasomy traced to meiosis and a third patient who appeared to have chromosome 1q trisomy with possible ties to mitotic cell division — suggested that five of the patients had brain-specific chromosome 1q alleles that were distinct from those found in their parents.
Together, the results were consistent with epilepsy-related chromosome 1q alterations that arose during meiosis but were subsequently rescued in non-brain tissues, the investigators explained, calling post-zygotic meiotic error rescue "an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains."
In particular, the analyses suggested that the chromosome 1q copy number changes stemmed from maternally-derived meiotic errors. Though they did not test for mosaic mutations across every tissue type, they found that the alterations were missing from blood or buccal cell samples but were enriched in the brain's astrocyte cells, where they coincided with a related gene expression signature and characteristic hyaline inclusion symptoms.
"The presence of the chr1q gain in brain tissue, while being absent from blood or buccal cells, underscores the fact that human development represents a complex interplay of developmental bottlenecks and proliferation advantages that are not yet fully understood," the authors wrote, adding that the findings "demonstrate a novel mechanism for the origin of brain chromosomal mosaicism and link brain mosaic chr1q gain to a distinct clinical phenotype including early-onset focal epilepsy, cortical malformation, and cytoplasmic hyaline astrocytic inclusions."