Phenotypic distinctions between mosaic forms of tuberoussclerosis complex

PurposeTo determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease.MethodsNext-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent...

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Published in:Genetics in medicine 2019-11, Vol.21 (11), p.2594-2604
Main Authors: Treichel, Alison M, Hamieh Lana, Nathan, Neera R, Tyburczy, Magdalena E, Ji-an, Wang, Oyerinde Oyetewa, Raiciulescu Sorana, Julien-Williams, Patricia, Jones, Amanda M, Gopalakrishnan Vissaagan, Moss, Joel, Kwiatkowski, David J, Darling, Thomas N
Format: Article
Language:English
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Tuberous sclerosis
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Summary:PurposeTo determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease.MethodsNext-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records.ResultsThe median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24 years, n = 7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10 years, n = 12), and germline TSC patients (10 findings, 4 years, n = 29). Cutaneous and internal organ involvement positively correlated in mosaic (R = 0.62, p = 0.005), but not germline (R = −0.24, p = 0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0–19%) positively correlated with the number of major features (R = 0.55, p = 0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC.ConclusionThe phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.
ISSN:1098-3600
1530-0366
DOI:10.1038/s41436-019-0520-3