Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing

Tyburczy, Magdalena E.; Dies, Kira; Glass, Jennifer; Camposano, Susana; Chekaluk, Yvonne; Thorner, Aaron R.; Li, Gang; Krueger, Darcy A.; Franz, David Neal; Thiele, Elizabeth A.; Şahin, Mustafa; Kwiatkowski, David J.

doi:10.1371/journal.pgen.1005637

Cited by 236 publications

(298 citation statements)

References 53 publications

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“…We demonstrate germline and somatic mutations 1) in TSC2 from non-TSC patients and 2) associated with HME. Our remaining cases with germline loss-of-function mutations may also contain “second hit” mutations that could represent large-scale CNVs undetectable by targeted sequencing, mutations in genes not included in our panel or in introns (Tyburczy et al, 2015a), or mutations below our detection limit.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

et al. 2017

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Summary Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27/66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA, and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional PIK3CA activation in mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

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Section: Discussionmentioning

confidence: 99%

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

et al. 2017

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“…It would be interesting to study genotypephenotype associations in a larger cohort of mosaic TSC patients, to determine whether these individuals are more likely to have specific types of pathology, as has been suggested previously. [25][26][27][28] Our cohort consisted of 40 individuals with a de novo mutation (12 TSC1, 28 TSC2), 12 individuals from 8 different families and 12 individuals (5 TSC1, 7 TSC2) for whom we did not have access to parental DNA. Familial TSC cases are reported to have a milder phenotype than sporadic TSC cases, although ascertainment bias cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

et al. 2016

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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. European Journal of Human Genetics (2016) 24, 1688-1695; doi:10.1038/ejhg.2016.85; published online 13 July 2016 INTRODUCTION Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder caused by inactivating TSC1 or TSC2 variants. 1,2 Most TSC-associated lesions are thought to arise due to somatic secondhit mutations that inactivate the remaining wild-type TSC1 or TSC2 allele. The protein products of TSC1 and TSC2 form the TSC complex, that inhibits the mammalian Target of Rapamycin Complex 1 (mTORC1). 3 Loss or inactivation of the TSC complex results in constitutive activation of mTORC1, and mTORC1 inhibitors have been shown to be useful for treating hamartoma-related complications of TSC. 4,5 Our aim was to investigate genotype-phenotype associations in a well-characterized cohort of TSC individuals, focusing on the relationships between specific TSC1 and TSC2 variants and macrostructural brain lesions detected by magnetic resonance imaging (MRI), including cortical tubers, radial migration lines (RMLs), subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs). In most studies, inactivating TSC2 variants are associated with increased numbers of cortical tubers and a higher prevalence of SEGAs. [6][7][8][9][10][11][12][13][14] We investigated whether there was additional clinical value for subdivision of TSC2 variants, as has been described recently for cognitive function in TSC. 15 We compared TSC-rel...

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“…Furthermore, despite our efforts to also discover somatic mutations in our data, our analysis was limited by both the read depth in our study, where only variants with an allele frequency of ∼ 0.10 or higher would be detected, and also by the availability of only DNA from whole blood, in which the mutation may not even be present. Results from a study of somatic mutations in tuberous sclerosis complex showed that a majority of the patients with somatic mosaicism had an allele frequency <0.10 in blood [Tyburczy et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Lund¹,

Striano

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et al. 2016

Mol Syndromol

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Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.

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Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing

Cited by 236 publications

References 53 publications

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

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