Pathogenic Somatic Variant in a Child With Tuberous Sclerosis Complex Without Pathogenic Variants in or .

OBJECTIVE

To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant in , but no pathogenic variants in the 2 known TSC genes, or .

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 or but identified a pathogenic somatic 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 are associated with focal cortical dysplasia and hemimegalencephaly. We propose that variants in may explain some of the genetically undiagnosed TSC cases and may be the third gene for TSC, or .