Pathogenic <i>RHEB</i> Somatic Variant in a Child With Tuberous Sclerosis Complex Without Pathogenic Variants in <i>TSC1</i> or <i>TSC2</i>.

Abstract

To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant in <i>RHEB</i>, but no pathogenic variants in the 2 known TSC genes, <i>TSC1</i> or <i>TSC2</i>. 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. 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 <i>TSC1</i> or <i>TSC2</i> but identified a pathogenic somatic <i>RHEB</i> variant (NM_005614.4:c.104_105delACinsTA [p.Tyr35Leu]) in the cortical tuber. RHEB is a partner of the TSC1/2 complex in the mechanistic target of rapamycin pathway. Somatic variants in <i>RHEB</i> are associated with focal cortical dysplasia and hemimegalencephaly. We propose that variants in <i>RHEB</i> may explain some of the genetically undiagnosed TSC cases and may be the third gene for TSC, or <i>TSC3</i>.