Deciphering Concurrent Tuberous Sclerosis Complex and Bipolar Disorder with a Genetic Approach

Tuberous sclerosis complex (TSC) is a rare genetic disorder that causes benign tumors to form in multiple organs and often begins in early childhood. TSC mainly occurs due to autosomal dominant mutations in the TSC1 or TSC2 genes, leading to an aberrant activation of mTOR signaling pathway. TSC is strongly associated with developmental neuropsychiatric disorders such as autism spectrum disorder and intellectual disability. However, only few publications have reported the concurrence of TSC with bipolar disorder (BD) and very little is known regarding the respective underlining mechanism(s). To address such gap in knowledge, we studied an individual who was diagnosed with TSC and BD by using a combination of gross anatomical, magnetic resonance imaging (MRI), and genetic approaches. The study results strongly confirmed a TSC diagnosis in the donor, with less certainty for BD. The genetic screening by whole exome sequencing (WES) on the Illumina next generation sequencing platform (NGS) yielded 77 modified genes with rare (minor allele frequency, MAF ≤ 0.01) and 64 modified genes with low-frequency (0.01 < MAF < 0.05) pathological/deleterious variants. The functional annotation of those genes allowed their grouping into 13 functional categories most relevant to the present case. The most interesting were several genes that participate in PI3K/AKT/mTOR signaling or mediate signaling pathways known to have a cross-talk with mTOR: Sonic hedgehog, Notch, and Wnt. Yet several affected genes were linked to BD/Schizophrenia, pointing toward a possible existence of polygenic components in both the TSC and BD. The strongly modified AHNAK2 potentially associated with both TSC and BD might indicate the existence of a pleiotropic component in the genetic underlining of the concurrent TSC and BD in the present case.