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 - 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 - https://www.scopus.com/pages/publications/85067027397
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 -