title: Genotype and brain pathology phenotype in children with tuberous sclerosis complex.
abstract: Structural brain malformations associated with Tuberous Sclerosis Complex (TSC) are related to the severity of the clinical symptoms and can be visualized by magnetic resonance imaging (MRI). Tuberous Sclerosis Complex is caused by inactivating TSC1 or TSC2 mutations. We investigated associations between TSC brain pathology and different inactivating TSC1 and TSC2 variants, and examined the potential prognostic value of subdivision of TSC2 variants based on their predicted effects on TSC2 expression. We performed genotype-phenotype associations of TSC-related brain pathology on a cohort of 64 children aged 1.4-17.9 years. Brain abnormalities were assessed using MRI. Individuals were grouped into those with an inactivating TSC1 variant and those with an inactivating TSC2 variant. The TSC2 group was subdivided into changes predicted to result in TSC2 protein expression (TSC2p) and changes predicted to prevent expression (TSC2x). The TSC2 group was associated with more and larger tubers, more radial migration lines, and more subependymal nodules than the TSC1 group. Subependymal nodules were also more likely to be calcified. Subdivision of the TSC2 group did not reveal additional, substantial differences, except for a larger number of tubers in the temporal lobe and a larger fraction of cystic tubers in the TSC2x subgroup. The severity of TSC-related brain pathology was related to the presence of an inactivating TSC2 variant. Although larger studies might find specific TSC2 variants that have prognostic value, in our cohort, subdivision of the TSC2 group did not lead to better prediction.
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE-TSC Expertise Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Overwater
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Swenker
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Emma L
authors.initials: EL
authors.lastname: van der Ende
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Kimberley Bm
authors.initials: KB
authors.lastname: Hanemaayer
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.affiliation: ENCORE-TSC Expertise Center, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Agnies M
authors.initials: AM
authors.lastname: van Eeghen
authors.affiliation: Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ans Mw
authors.initials: AM
authors.lastname: van den Ouweland
authors.affiliation: ENCORE-TSC Expertise Center, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Henriëtte A
authors.initials: HA
authors.lastname: Moll
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE-TSC Expertise Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marie-Claire Y
authors.initials: MY
authors.lastname: de Wit
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010641:Phenotype; D014402:Tuberous Sclerosis / Q000175:diagnosis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins