Abstracts

Rationale: Periventricular nodular heterotopia (PVNH) is a common structural malformation of cortical development that is frequently accompanied by intractable epilepsy. About 8% -26% of familial cases of PNH are explained by mutations in Filamin A (FLNA), an X-linked gene involved in cytoskeleton organization. Many patients do not have a genetic explanation for their disorder, because somatic mosaicism results in a pathogenic variant that is restricted to brain tissue and is not detected by genomic analysis of peripheral samples. If genetic testing in a blood sample is negative, the patients remain undiagnosed. We utilized trace tissue adherent to diagnostic stereotactically placed depth EEG electrodes to perform whole exome sequencing, and we identified a novel candidate gene for PVNH, MEN1.  Methods: This study was approved by the Insititutional Review Board at Baylor College of Medicine (IRB H-13798), and the patient was consented. Genomic DNA was amplified from cells that remained attached to stereotactically-placed depth EEG (SEEG) electrodes after surgical removal. DNA quality was verified by Tapestation (Agilent), and then submitted for whole exome sequencing (WES) that generated more than 7GB of data. WES analysis of SEEG-derived DNA of pathologic tissue was compared to DNA derived from peripheral tissue, and relevant variants identified were validated by Sanger sequencing. Results: We evaluated a patient with PVNH and medically refractory epilepsy. He was considered for epilepsy surgery, and SEEG electrodes targeting PNH and additional targets were implanted. In a tissue stripped from the SEEG electrode, we uncovered a de novo heterozygous pathogenic variant in a novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1) (c.1546dupC, p.R516PfsX15). This variant was absent in an earlier exome profiling of the venous blood-derived DNA. MEN1 is a known tumor suppressor gene that encodes the nuclear scaffold protein menin, and has a regulatory role in transcription, proliferation, differentiation, and genomic integrity. Conclusions: We piloted a novel, minimally-invasive DNA collection method that utilizes established clinical diagnostic paradigm of epilepsy, and we uncovered a novel candidate gene for sporadic PVNH. Our method has the potential to aid in diagnostics of epilepsy patients with focal epilepsy that would otherwise remain undiagnosed due to inaccessibility of pathogenic tissue. Funding: NIH/NINDS 1 U01 NS090406NIH/NINDS 1 U01 NS090362