TY - JOUR
T1 - TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants
T2 - results of the EPISTOP study
AU - Ogórek, Barbara
AU - Hamieh, Lana
AU - Hulshof, Hanna M
AU - Lasseter, Kathryn
AU - Klonowska, Katarzyna
AU - Kuijf, Hugo
AU - Moavero, Romina
AU - Hertzberg, Christoph
AU - Weschke, Bernhard
AU - Riney, Kate
AU - Feucht, Martha
AU - Scholl, Theresa
AU - Krsek, Pavel
AU - Nabbout, Rima
AU - Jansen, Anna C
AU - Benova, Barbora
AU - Aronica, Eleonora
AU - Lagae, Lieven
AU - Curatolo, Paolo
AU - Borkowska, Julita
AU - Sadowski, Krzysztof
AU - Domańska-Pakieła, Dorota
AU - Janson, Stef
AU - Kozlowski, Piotr
AU - Urbanska, Malgorzata
AU - Jaworski, Jacek
AU - Jozwiak, Sergiusz
AU - Jansen, Floor E
AU - Kotulska, Katarzyna
AU - Kwiatkowski, David J
N1 - Funding Information:
We thank all the patients and their families who participated in this study, all medical staff members who contributed to collection of clinical information, Karthik V. Karnik for his help with the customized computational code for variant detection and reporting, and The Center for Cancer Genomics at Dana-Farber Cancer Institute for help with targeted capture sequencing. This work was supported by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 602391, Polish Ministerial funds for science (years 2014–2019) for the implementation of international co-financed projects, and the Engles Family LAM/TS Research Fund.
Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
PY - 2020/9
Y1 - 2020/9
N2 - Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
AB - Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
KW - Child, Preschool
KW - Humans
KW - Infant
KW - Mosaicism
KW - Mutation
KW - Phenotype
KW - Tuberous Sclerosis Complex 1 Protein/genetics
KW - Tuberous Sclerosis Complex 2 Protein/genetics
KW - Tuberous Sclerosis/diagnostic imaging
KW - TSC2
KW - TSC1
KW - clinical manifestations
KW - mosaicism
KW - tuberous sclerosis complex (TSC)
UR - http://www.scopus.com/inward/record.url?scp=85085526578&partnerID=8YFLogxK
U2 - 10.1038/s41436-020-0823-4
DO - 10.1038/s41436-020-0823-4
M3 - Article
C2 - 32461669
SN - 1098-3600
VL - 22
SP - 1489
EP - 1497
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 9
ER -