TY - JOUR
T1 - Low-level mosaicism in tuberous sclerosis complex
T2 - prevalence, clinical features, and risk of disease transmission
AU - Giannikou, Krinio
AU - Lasseter, Kathryn D.
AU - Grevelink, Joannes M.
AU - Tyburczy, Magdalena E.
AU - Dies, Kira A.
AU - Zhu, Zachary
AU - Hamieh, Lana
AU - Wollison, Bruce M.
AU - Thorner, Aaron R.
AU - Ruoss, Stephen J.
AU - Thiele, Elizabeth A.
AU - Sahin, Mustafa
AU - Kwiatkowski, David J.
N1 - Funding Information:
The authors thank all subjects in this study; the clinicians who referred and evaluated the patients; Karthik V. Karnik, Rachel E. Yan, and Edward R. Kwiatkowski for their work on customized code for MPS analysis; and the Tuberous Sclerosis Alliance and the TSC Natural History Database Consortium. Supported by The Engles Family Fund for Research in TSC and LAM. The views expressed in this article are those of the authors and do not necessarily reflect the opinion of the Tuberous Sclerosis Alliance or the Tuberous Sclerosis Complex Natural History Database Consortium.
Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk. Methods: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples. Results: TSC mosaic patients (MVAF: 0–10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically. Conclusion: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.
AB - Purpose: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk. Methods: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples. Results: TSC mosaic patients (MVAF: 0–10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically. Conclusion: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.
KW - TSC1
KW - TSC2
KW - mosaicism
KW - transmission risk
KW - tuberous sclerosis complex
UR - http://www.scopus.com/inward/record.url?scp=85067027397&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0562-6
DO - 10.1038/s41436-019-0562-6
M3 - Article
C2 - 31160751
AN - SCOPUS:85067027397
SN - 1098-3600
VL - 21
SP - 2639
EP - 2643
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -