Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family

Background Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss‐of‐function of either TSC1 or TSC2 gene. However, in 10%–15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing. Methods In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single‐gene tests. Results Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3′‐end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1. Conclusions In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy‐neutral variant was missed by the TSC1 and TSC2 single‐gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC. We report a family presenting classical tuberous sclerosis phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9.