TY - JOUR
T1 - Phenotypic distinctions between mosaic forms of tuberous sclerosis complex
AU - Treichel, Alison M.
AU - Hamieh, Lana
AU - Nathan, Neera R.
AU - Tyburczy, Magdalena E.
AU - Wang, Ji an
AU - Oyerinde, Oyetewa
AU - Raiciulescu, Sorana
AU - Julien-Williams, Patricia
AU - Jones, Amanda M.
AU - Gopalakrishnan, Vissaagan
AU - Moss, Joel
AU - Kwiatkowski, David J.
AU - Darling, Thomas N.
N1 - Funding Information:
Research reported in this publication was supported in part by the Intramural Research Program, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI); the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, under award number R01AR062080; NIH, NHLBI under award number 1U01HL131022; the Doris Duke Charitable Foundation Clinical Research Mentorship grants 2014088 and 2018042; the Tuberous Sclerosis Alliance, Engles Fund for Research in TSC and LAM. Additionally, this work was made possible through the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate–Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. Written consent was obtained to publish the photography of the patients included in Fig. 1.
Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. Methods: Next-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. Results: The 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. Conclusion: The 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.
AB - Purpose: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. Methods: Next-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. Results: The 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. Conclusion: The 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.
KW - angiofibroma
KW - genodermatosis
KW - mosaic
KW - segmental
KW - tuberous sclerosis complex
UR - http://www.scopus.com/inward/record.url?scp=85066137905&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0520-3
DO - 10.1038/s41436-019-0520-3
M3 - Article
C2 - 31114024
AN - SCOPUS:85066137905
SN - 1098-3600
VL - 21
SP - 2594
EP - 2604
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -