Investigating the Role of CCT8 Somatic Variants in Polymicrogyria

Polymicrogyria (PMG) is a brain malformation which involves an excessive amount of small brain folding patterns which frequently leads to epilepsy. About 20-30% of PMG cases can be caused by germline de novo variants that likely arise in the gametes of the parents, but many instances of PMG remain without a genetic explanation. One hypothesis is that PMG can be explained as cases that may be caused by new variants that arise during embryonic brain development and are present only in particular brain cells. In this study, we seek to determine the role of somatic variants in PMG, due the recent relevance of such variants in a variety of neurological disorders. We have generated a high-quality dataset of DNA extracted from brain tissue and blood from 13 PMG patients to evaluate the role of somatic variants. We then went on to create sequencing libraries and generated high quality sequencing data across 265 candidate genes involved in the mTOR signaling pathways and/or neurodevelopmental disease. We have identified novel candidate somatic variants in CCT8, a gene that encodes a subunit of the chaperonin containing TCP-1 (CCT/TRiC) complex, which is essential for the proper folding of cytoskeletal proteins such as actin and tubulin. Somatic variants in epilepsy are often associated with mTOR pathway genes. The CCT complex is related to the mTOR pathway because it plays a key role in folding necessary subunits of mTOR complexes. Understanding the role of somatic mutations in brain malformations could improve diagnosis and treatment strategies for individuals with epilepsy and other neurodevelopmental disorders.