32593 Diagnosis of mosaic tuberous sclerosis complex using next-generation sequencing of subtle or unusual cutaneous findings

Abstract

Background: Individuals with mosaic tuberous sclerosis complex (TSC) may present later in life, with few classic findings, and negative genetic results by conventional testing of blood. Thus, genetic analysis of samples obtained from affected skin, which show higher allele fractions for the mosaic pathogenic variant than blood, can be critical for diagnosis of mosaic TSC. Methods: Three individuals with pulmonary lymphangioleiomyomatosis (LAM), which may occur in women with TSC (TSC-LAM) or sporadically (S-LAM), underwent evaluation for TSC-associated mucocutaneous and internal findings. We used our previously published algorithm to confirm clinical suspicion for mosaicism and guide selection of tissue specimens and genetic workup. Next-generation sequencing (NGS) of cutaneous findings was used to confirm clinical suspicion of mosaic TSC. Results: Two individuals previously thought to have S-LAM were diagnosed with mosaic TSC-LAM upon NGS of unilateral angiofibromas in one patient and an unusual cutaneous hamartoma in the other. A third individual, diagnosed with TSC in childhood, was found to have a mosaic pathogenic variant in TSC2 in cutaneous tissue from a digit with macrodactyly. Conclusion: NGS of subtle or unusual TSC-associated skin findings may enhance detection of mosaicism and is important due to implications regarding surveillance, prognosis, and risk of transmission to offspring. As NGS becomes increasingly available for commercial use, dermatologists may be increasingly called upon to provide skin samples for genetic analysis. NGS has the potential to enhance detection of mosaicism in TSC and other genodermatosis with mosaic manifestations.