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Abstract
Objective To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant in RHEB, but no pathogenic variants in the 2 known TSC genes, TSC1 or TSC2.
Methods We present the clinical and imaging findings in a child presenting with drug-resistant focal seizures and multiple cortical tubers, a subependymal giant cell astrocytoma and multiple subependymal nodules in 1 cerebral hemisphere. Targeted panel sequencing and exome sequencing were performed on genomic DNA derived from blood and resected tuber tissue.
Results The child satisfied clinical diagnostic criteria for TSC, having 3 major features, only 2 of which are required for diagnosis. Genetic testing did not identify pathogenic variants or copy number variations in TSC1 or TSC2 but identified a pathogenic somatic RHEB variant (NM_005614.4:c.104_105delACinsTA [p.Tyr35Leu]) in the cortical tuber.
Discussion RHEB is a partner of the TSC1/2 complex in the mechanistic target of rapamycin pathway. Somatic variants in RHEB are associated with focal cortical dysplasia and hemimegalencephaly. We propose that variants in RHEB may explain some of the genetically undiagnosed TSC cases and may be the third gene for TSC, or TSC3.
Footnotes
Submitted and externally peer reviewed. The handling editor was Associate Editor Courtney Wusthoff, MD, MS.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received October 10, 2022.
- Accepted in final form January 26, 2023.
- © 2023 American Academy of Neurology
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