TY - JOUR
T1 - Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex
AU - Klonowska, Katarzyna
AU - Giannikou, Krinio
AU - Grevelink, Joannes M.
AU - Boeszoermenyi, Barbara
AU - Thorner, Aaron R.
AU - Herbert, Zachary T.
AU - Afrin, Antara
AU - Treichel, Alison M.
AU - Hamieh, Lana
AU - Kotulska, Katarzyna
AU - Jozwiak, Sergiusz
AU - Moss, Joel
AU - Darling, Thomas N.
AU - Kwiatkowski, David J.
N1 - Publisher Copyright:
© 2023 American Society of Human Genetics
PY - 2023/6/1
Y1 - 2023/6/1
N2 - Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%–15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.
AB - Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%–15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.
KW - TSC angiofibroma
KW - TSC angiomyolipoma
KW - TSC1
KW - TSC2
KW - low-level mosaicism
KW - massively parallel sequencing
KW - tuberous sclerosis complex
KW - variant detection
UR - http://www.scopus.com/inward/record.url?scp=85160283721&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2023.04.002
DO - 10.1016/j.ajhg.2023.04.002
M3 - Article
C2 - 37141891
AN - SCOPUS:85160283721
SN - 0002-9297
VL - 110
SP - 979
EP - 988
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -