Journal article

Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy

Wei Shern Lee, Sarah EM Stephenson, Kate Pope, Greta Gillies, Wirginia Maixner, Emma Macdonald-Laurs, Duncan MacGregor, Colleen D'Arcy, Graeme Jackson, A Simon Harvey, Richard J Leventer, Paul J Lockhart



OBJECTIVE: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown. METHODS: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry. RESULTS: Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTO..

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

This study was funded by the National Health and Medical Research Council (GNT1128933 and GNT1161549) and Murdoch Children's Research Institute. Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. R.J. Leventer is supported by the Melbourne Children's Clinician Scientist Fellowship scheme and P.J. Lockhart is supported by the Vincent Chiodo Foundation. This study was not industry-sponsored.