Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings

R. C. Caylor, L. Grote, I. Thiffault, E. G. Farrow, L. Willig, S. Soden, S. M. Amudhavalli, A. J. Nopper, K. A. Horii, E. Fleming, J. Jenkins, H. Welsh, M. Ilyas, K. Engleman, A. Abdelmoity, C. J. Saunders

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3.) Pathogenic variants in TSC1 or TSC2 were identified in nine individuals, including relatives with limited or no medical concerns at the time of testing. Of the nine individuals reported here, six had post-diagnosis examinations and three met clinical diagnostic criteria for TSC. One did not meet clinical criteria for a possible or definite diagnosis of TSC, and two had only a possible clinical diagnosis following post-diagnosis workup. These individuals as well as their mothers demonstrated limited features that would not raise concern for TSC in the absence of molecular results. In addition, three individuals exhibited epilepsy with normal brain MRIs, and two without seizures or intellectual disability had MRI findings fulfilling major criteria for TSC highlighting the difficulty providers face when relying on clinical criteria to guide genetic testing. Given the importance of a timely TSC diagnosis for clinical management, such cases demonstrate a potential benefit for clinical criteria to include seizures and an unbiased molecular approach to genetic testing.