Authors :
Presenting Author: Tracy Bedrosian, PhD – Nationwide Children's Hospital
Katherine Miller, PhD – Nationwide Children's Hospital; Adithe Rivaldi, B.S. – Nationwide Children's Hospital; Noriyuki Shinagawa, B.S. – Nationwide Children's Hospital; Jason Navarro, B.S. – Nationwide Children's Hospital; Sahib Sran, M.S. – Nationwide Children's Hospital; Jesse Westfall, M.S. – Nationwide Children's Hospital; Anthony Miller, Ph.D. – Nationwide Children's Hospital; Ryan Roberts, M.D., Ph.D. – Nationwide Children's Hospital; Yassmine Akkari, Ph.D. – Nationwide Children's Hospital; Rachel Supinger, M.S. – Nationwide Children's Hospital; Mark Hester, Ph.D. – Nationwide Children's Hospital; Mohammad Marhabaie, Ph.D. – Nationwide Children's Hospital; Meethila Gade, B.S. – University of North Carolina, Chapel Hill; Jinfeng Lu, M.D. – Columbia University; Olga Rodziyevska, M.D. – McGovern Medical School; Meenakshi Bhattacharjee, M.D. – McGovern Medical School; Gretchen Von Allmen, M.D. – McGovern Medical School; Edward yang, M.D. – Boston Children's Hospital; Hart Lidov, M.D. – Boston Children's Hospital; Chellamani Harini, M.D. – Boston Children's Hospital; manish Shah, M.D. – McGovern Medical School; Jeffrey Leonard, M.D. – Nationwide Children's Hospital; Jonathan Pindrik, M.D. – Nationwide Children's Hospital; Ammar Shaikhouni, M.D., Ph.D. – Nationwide Children's Hospital; James Goldman, M.D., Ph.D. – Columbia University; Christopher Pierson, M.D., Ph.D. – Nationwide Children's Hospital; Diana Thomas, M.D., Ph.D. – Nationwide Children's Hospital; Daniel Boue, M.D., Ph.D. – Nationwide Children's Hospital; Adam Ostendorf, M.D. – Nationwide Children's Hospital; Elaine Mardis, Ph.D. – Nationwide Children's Hospital; Annapurna Poduri, M.D., MPH – Boston Children's Hospital; Daniel Koboldt, M.S. – Nationwide Children's Hospital; Erin Heinzen, Ph.D., Pharm.D. – University of North Carolina, Chapel Hill
Rationale:
Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Notably, mosaic copy number gains of the entire q-arm of chromosome 1 have been identified in brain tissue from pediatric patients with severe neurodevelopmental delay, unilateral polymicrogyria or focal cortical dysplasia, and early-onset focal epilepsy. Although it has been presumed that these alterations are post-zygotic due to their mosaic allele fraction and absence from blood samples, their origin has not been investigated. Methods:
We characterized surgically resected brain tissue from six pediatric epilepsy patients and identified somatic mosaic copy number gains of chromosome 1q.Results:
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. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions.Conclusions:
These results support a novel genetic association for astrocytic inclusions in epilepsy. Further, these data
demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.Funding:
The Nationwide Innovation Fund, L. B. Research and Education Foundation (NS), NIH-NINDS (R01NS094596) to ELH, and NIH-NINDS (R01NS129784) to TAB.