Journal article

Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia

Wei Shern Lee, Sara Baldassari, Mathilde Chipaux, Homa Adle-Biassette, Sarah EM Stephenson, Wirginia Maixner, A Simon Harvey, Paul J Lockhart, Stephanie Baulac, Richard J Leventer

Annals of Clinical and Translational Neurology | WILEY | Published : 2021


Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain dir..

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Awarded by National Health and Medical Research Council

Awarded by European Research Council

Awarded by Investissements d'avenir

Funding Acknowledgements

This study was funded by the National Health and Medical Research Council (GNT1128933 to RJL and PJL and GNT1161549 to PJL and RJL), European Research Council (No682345 to SB), "Investissements d'avenir" (ANR-10-IAIHU-06 and ANR-18-RHUS-0005 to SB) and the Brain Foundation (to RJL). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. RJL is supported by a Melbourne Children's Clinician Scientist Fellowship. PJL is supported by the Vincent Chiodo Foundation. WSL is supported by the Melbourne Research Scholarship and the Research Training Program Scholarship. This study was not industry sponsored.