Affiliation:
1. Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary
2. Department of Medical Genetics, Cumming School of Medicine, University of Calgary
3. Alberta Children’s Hospital Research Institute, University of Calgary
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.
Funder
Alberta Children’s Hospital Foundation
U of C | Alberta Children’s Hospital Research Institute
Gouvernement du Canada | Canadian Institutes of Health Research
Publisher
Life Science Alliance, LLC