Somatic mosaicism is the accumulation of mutations in DNA sequence or copy number in cellular genomes after fertilization. It is a known cause of neurological disorders including developmental brain malformations and epilepsy. Now, in a new study researchers from Nationwide Children’s Hospital discovered an alternate origin of brain mosaicism in some children with focal epilepsy.
The findings are published in Nature Genetics in an article titled, “Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.”
“Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy,” wrote the researchers. “Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients.”
“About 1 in every 26 people will have epilepsy at some point in their lives. The causes are incredibly diverse, and a mystery in over half of people with epilepsy,” said Adam Ostendorf, MD, a pediatric neurologist at Nationwide Children’s and an author of the study.
About a third of children with epilepsy have drug-resistant seizures that greatly affect their quality of life, safety, and developmental outcomes. “We were motivated to study the genetic causes of drug-resistant epilepsy so future research might be able to develop more effective treatments,” explained Tracy Bedrosian, PhD, senior author of the paper and principal investigator at the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital.
The researchers performed a genetic analysis of brain tissue, blood, and buccal cells. Tissue samples were from six patients, ages two months to seven months, who underwent epilepsy surgery. The brain samples showed that some of the cells in the brain tissue (including astrocytes) had extra copies of chromosome 1q compared to the normal tissue. The blood and buccal cells did not have any cells with extra copies.
Astrocytes carrying the extra 1q showed distinct gene expression signatures and histopathologic differences such as hyaline inclusions. This evidence supports the association of chromosome 1q gains with astrocytic inclusions in epilepsy.
However, that etiology wasn’t the only finding in the study.
“The surprising finding was that the genetic alteration (chromosome 1q gains) was inherited in some of the patients, even though it was only found in a mosaic pattern within brain tissue,” Bedrosian added. “This finding was a serendipitous observation that led us down a path to discover a novel mechanism for brain mosaicism.”
“We were able to genetically analyze blood from the mothers and then confirm that the extra chromosomal material was actually inherited, indicating a complex genetic phenomenon that resulted in the somatic mosaicism,” said Katherine Miller, PhD, first author of the study and principal investigator at the Institute for Genomic Medicine.
Normally, mosaicism is expected to be the result of changes to the genetic material during fetal development. However, these data demonstrate an alternate mechanism of brain chromosomal mosaicism—where the increase in copy number was inherited as the result of a meiotic error. During fetal development, these copy number gains were corrected in other cell lineages, making the copy number increase undetectable in blood and buccal cells.