Tuberous sclerosis complex (TSC) is a genetic syndrome due to mutations in either TSC1 or TSC2, leading to the development of hamartomatous tumours at multiple body sites, including facial skin (facial angiofibroma (FAF)), brain (cortical tubers) and kidney (angiomyolipoma (AML)). In this report, we describe an individual with minimal TSC clinical features, who had ‘no mutation identified’ (NMI) by prior genetic testing in a clinical laboratory. Our massively parallel sequencing (MPS) analysis of multiple samples from different body sites and tumours (including blood, saliva, normal skin, AML and FAF) revealed an extraordinary situation in which FAF and AML had completely independent inactivating biallelic variants in TSC2, not present in other matched samples. This suggests that the two different lesions (AML and FAF) are not due to the same underlying germline or mosaic mutation, rather both are likely sporadic events. This case demonstrates the relevance of thorough clinical examination, high-coverage MPS of multiple tumours and matched normal tissues, and appropriate genetic counselling for individuals with marginal TSC features and possible TSC1 or TSC2 mosaicism.
- genetic counseling
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Correction notice This article has been corrected since it was published Online First. The caption of figure 1 has been amended for clarity.
Contributors KK conceptualised the study, performed DNA extraction from all analysed samples, prepared amplicon MPS libraries, performed computational analysis of the MPS data and interpreted the results, wrote the manuscript and prepared the table and figure, acquired funding for the study. EAT performed clinical and imaging evaluation. JMG performed clinical evaluation and collected skin biopsies. ART participated in MPS data generation and preprocessing. DJK conceptualised and supervised the study, performed clinical evaluation, reviewed and participated in writing the manuscript, acquired funding for the study. All authors read and approved the manuscript.
Funding The study was funded by FY2020 TSC Alliance Postdoctoral Fellowship Award (KK) and Engles Family Fund for Research in TSC and LAM (DJK).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.