Single variant, yet “double trouble”: TSC and KBG syndrome because of a large de novo inversion

Abstract

Despite the advances in high-throughput sequencing, many rare disease patients remain undiagnosed. In particular, the patients with well-defined clinical phenotypes and established clinical diagnosis, yet missing or partial genetic diagnosis, may hold a clue to more complex genetic mechanisms of a disease that could be missed by available clinical tests. Here, we report a patient with a clinical diagnosis of Tuberous sclerosis, combined with unusual secondary features, but negative clinical tests includingTSC1andTSC2. Short-read whole-genome sequencing combined with advanced bioinformatics analyses were successful in uncovering a de novo pericentric 87-Mb inversion with breakpoints inTSC2andANKRD11, which explains the TSC clinical diagnosis, and confirms a second underlying monogenic disorder, KBG syndrome. Our findings illustrate how complex variants, such as large inversions, may be missed by clinical tests and further highlight the importance of well-defined clinical diagnoses in uncovering complex molecular mechanisms of a disease, such as complex variants and “double trouble” effects.