{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:35:39Z","timestamp":1791477339047,"version":"4.3.4"},"reference-count":154,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype\u2013phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1\/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.<\/jats:p>","DOI":"10.3390\/genes15030332","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:31:12Z","timestamp":1709530272000},"page":"332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions"],"prefix":"10.3390","volume":"15","author":[{"given":"Alice","family":"Man","sequence":"first","affiliation":[{"name":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-3739","authenticated-orcid":false,"given":"Matteo","family":"Di Scipio","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Grewal","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3966-3771","authenticated-orcid":false,"given":"Yujin","family":"Suk","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5859-652X","authenticated-orcid":false,"given":"Elisabetta","family":"Trinari","sequence":"additional","affiliation":[{"name":"Division of Developmental Pediatrics, Department of Pediatrics, McMaster Children\u2019s Hospital, Hamilton, ON L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Resham","family":"Ejaz","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6851-0646","authenticated-orcid":false,"given":"Robyn","family":"Whitney","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13023-019-1090-9","article-title":"Correction to: Incidence of Tuberous Sclerosis and Age at First Diagnosis: New Data and Emerging Trends from a National, Prospective Surveillance Study","volume":"14","author":"Mann","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","unstructured":"Northrup, H., Koenig, M.K., Pearson, D.A., and Au, K.S. (2021). Tuberous Sclerosis Complex, University of Washington."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pediatrneurol.2021.09.017","article-title":"Epilepsy Management in Tuberous Sclerosis Complex: Existing and Evolving Therapies and Future Considerations","volume":"126","author":"Zak","year":"2022","journal-title":"Pediatr. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13023-019-1258-3","article-title":"A Systematic Review on the Burden of Illness in Individuals with Tuberous Sclerosis Complex (TSC)","volume":"15","author":"Franz","year":"2020","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/dmcn.13352","article-title":"Causes of Mortality in Individuals with Tuberous Sclerosis Complex","volume":"59","author":"Amin","year":"2017","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/ajmg.c.31651","article-title":"Genetics, Genomics, and Genotype-Phenotype Correlations of TSC: Insights for Clinical Practice","volume":"178","author":"Peron","year":"2018","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000515672","article-title":"Current Approaches and Future Directions for the Treatment of MTORopathies","volume":"43","author":"Karalis","year":"2021","journal-title":"Dev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"fcab222","DOI":"10.1093\/braincomms\/fcab222","article-title":"Epilepsy in the MTORopathies: Opportunities for Precision Medicine","volume":"3","author":"Moloney","year":"2021","journal-title":"Brain Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"664695","DOI":"10.3389\/fnana.2021.664695","article-title":"Convergent and Divergent Mechanisms of Epileptogenesis in MTORopathies","volume":"15","author":"Nguyen","year":"2021","journal-title":"Front. Neuroanat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a022442","DOI":"10.1101\/cshperspect.a022442","article-title":"MTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development","volume":"5","author":"Crino","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s00401-019-02061-5","article-title":"Dissecting the Genetic Basis of Focal Cortical Dysplasia: A Large Cohort Study","volume":"138","author":"Baldassari","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/joa.12956","article-title":"New Insights into a Spectrum of Developmental Malformations Related to MTOR Dysregulations: Challenges and Perspectives","volume":"235","author":"Bongaarts","year":"2019","journal-title":"J. Anat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/ana.23943","article-title":"TORC1-Dependent Epilepsy Caused by Acute Biallelic Tsc1 Deletion in Adult Mice","volume":"74","author":"Abs","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"MTOR at the Nexus of Nutrition, Growth, Ageing and Disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"MTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nature21423","article-title":"KICSTOR Recruits GATOR1 to the Lysosome and Is Necessary for Nutrients to Regulate MTORC1","volume":"543","author":"Wolfson","year":"2017","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.det.2016.07.001","article-title":"Mosaic Disorders of the PI3K\/PTEN\/AKT\/TSC\/MTORC1 Signaling Pathway","volume":"35","author":"Nathan","year":"2017","journal-title":"Dermatol. Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1212\/NXG.0000000000000118","article-title":"Germline and Somatic Mutations in the MTOR Gene in Focal Cortical Dysplasia and Epilepsy","volume":"2","author":"Weckhuysen","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/ana.24444","article-title":"Somatic Mutations in the MTOR Gene Cause Focal Cortical Dysplasia Type IIb","volume":"78","author":"Nakashima","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrneurol.2016.81","article-title":"The MTOR Signalling Cascade: Paving New Roads to Cure Neurological Disease","volume":"12","author":"Crino","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2012.10.021","article-title":"Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes","volume":"92","author":"Orloff","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nature05933","article-title":"A Transforming Mutation in the Pleckstrin Homology Domain of AKT1 in Cancer","volume":"448","author":"Carpten","year":"2007","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling: Navigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.neuron.2012.03.010","article-title":"Somatic Activation of AKT3 Causes Hemispheric Developmental Brain Malformations","volume":"74","author":"Poduri","year":"2012","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/ng.2331","article-title":"De Novo Germline and Postzygotic Mutations in AKT3, PIK3R2 and PIK3CA Cause a Spectrum of Related Megalencephaly Syndromes","volume":"44","author":"Mirzaa","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1158\/1535-7163.MCT-10-0994","article-title":"PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K\/AKT\/MTOR Axis Inhibitors","volume":"10","author":"Janku","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/cge.12188","article-title":"AKT3 and PIK3R2 Mutations in Two Patients with Megalencephaly-Related Syndromes: MCAP and MPPH","volume":"85","author":"Nakamura","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1212\/WNL.0000000000207177","article-title":"Pathogenic RHEB Somatic Variant in a Child With Tuberous Sclerosis Complex Without Pathogenic Variants in TSC1 or TSC2","volume":"101","author":"Lee","year":"2023","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1874-6047(10)27003-8","article-title":"Rheb G-Proteins and the Activation of MTORC1","volume":"27","author":"Parmar","year":"2010","journal-title":"Enzymes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20080281","article-title":"The TSC1-TSC2 Complex: A Molecular Switchboard Controlling Cell Growth","volume":"412","author":"Huang","year":"2008","journal-title":"Biochem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/humu.22529","article-title":"TBC1D7 Mutations Are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease","volume":"35","author":"Alfaiz","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1136\/jmedgenet-2013-101680","article-title":"Disruption of TBC1D7, a Subunit of the TSC1-TSC2 Protein Complex, in Intellectual Disability and Megalencephaly","volume":"50","author":"Tcherkezian","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1111\/cge.12311","article-title":"A Recurrent Mutation in DEPDC5 Predisposes to Focal Epilepsies in the French-Canadian Population","volume":"86","author":"Martin","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/ana.24126","article-title":"Mutations in Mammalian Target of Rapamycin Regulator DEPDC5 Cause Focal Epilepsy with Brain Malformations","volume":"75","author":"Scheffer","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1212\/NXG.0000000000000028","article-title":"Two Definite Cases of Sudden Unexpected Death in Epilepsy in a Family with a DEPDC5 Mutation","volume":"1","author":"Nascimento","year":"2015","journal-title":"Neurol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1093\/hmg\/ddac225","article-title":"Germline Homozygous Missense DEPDC5 Variants Cause Severe Refractory Early-Onset Epilepsy, Macrocephaly and Bilateral Polymicrogyria","volume":"32","author":"Ververi","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1136\/jmedgenet-2016-103883","article-title":"GATOR1 Complex: The Common Genetic Actor in Focal Epilepsies","volume":"53","author":"Baldassari","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/ana.24547","article-title":"Mutations in the Mammalian Target of Rapamycin Pathway Regulators NPRL2 and NPRL3 Cause Focal Epilepsy","volume":"79","author":"Ricos","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1111\/epi.13391","article-title":"Involvement of GATOR Complex Genes in Familial Focal Epilepsies and Focal Cortical Dysplasia","volume":"57","author":"Weckhuysen","year":"2016","journal-title":"Epilepsia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.1093\/brain\/awac044","article-title":"NPRL3 Loss Alters Neuronal Morphology, MTOR Localization, Cortical Lamination and Seizure Threshold","volume":"145","author":"Iffland","year":"2022","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1073\/pnas.96.5.2110","article-title":"Regulation of G1 Progression by the PTEN Tumor Suppressor Protein Is Linked to Inhibition of the Phosphatidylinositol 3-Kinase\/Akt Pathway","volume":"96","author":"Ramaswamy","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/j.jaci.2016.03.055","article-title":"Phosphatase and Tensin Homolog (PTEN) Mutation Can Cause Activated Phosphatidylinositol 3-Kinase \u03b4 Syndrome-like Immunodeficiency","volume":"138","author":"Tsujita","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1086\/377109","article-title":"Germline PTEN Promoter Mutations and Deletions in Cowden\/Bannayan-Riley-Ruvalcaba Syndrome Result in Aberrant PTEN Protein and Dysregulation of the Phosphoinositol-3-Kinase\/Akt Pathway","volume":"73","author":"Zhou","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1002\/ana.25904","article-title":"Polymicrogyria Is Associated With Pathogenic Variants in PTEN","volume":"88","author":"Shao","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fendo.2018.00338","article-title":"PTEN: Tumor Suppressor and Metabolic Regulator","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1097\/MCD.0000000000000368","article-title":"Homozygous Missense STRADA Mutation in a Patient with Polyhydramnios, Megalencephaly and Symptomatic Epilepsy Syndrome","volume":"30","author":"Aerden","year":"2021","journal-title":"Clin. Dysmorphol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1002\/ajmg.a.37727","article-title":"Whole Exome Sequencing Identifies the First STRADA Point Mutation in a Patient with Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy Syndrome (PMSE)","volume":"170","author":"Bi","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2013.07.005","article-title":"Biallelic SZT2 Mutations Cause Infantile Encephalopathy with Epilepsy and Dysmorphic Corpus Callosum","volume":"93","author":"Hershkovitz","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/cge.13061","article-title":"Novel Biallelic SZT2 Mutations in 3 Cases of Early-Onset Epileptic Encephalopathy","volume":"93","author":"Tsuchida","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cattelani, C., Lesiak, D., Liebscher, G., Singer, I.I., Stasyk, T., Walln\u00f6fer, M.H., Heberle, A.M., Corti, C., Hess, M.W., and Pfaller, K. (2021). The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. Cells, 10.","DOI":"10.3390\/cells10102711"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ajhg.2013.10.001","article-title":"Mutations in KPTN Cause Macrocephaly, Neurodevelopmental Delay, and Seizures","volume":"94","author":"Baple","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1002\/ajmg.a.61778","article-title":"Pathogenic Variants in KPTN, a Rare Cause of Macrocephaly and Intellectual Disability","volume":"182","author":"Fernandez","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/ajmg.a.37105","article-title":"Novel Homozygous Mutation in KPTN Gene Causing a Familial Intellectual Disability-Macrocephaly Syndrome","volume":"167A","author":"Pajusalu","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the Tuberous Sclerosis Gene TSC1 on Chromosome 9q34","volume":"277","author":"Hermans","year":"1997","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ramlaul, K., Fu, W., Li, H., de Martin Garrido, N., He, L., Trivedi, M., Cui, W., Aylett, C.H.S., and Wu, G. (2021). Architecture of the Tuberous Sclerosis Protein Complex. J. Mol. Biol., 433.","DOI":"10.1016\/j.jmb.2020.166743"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Santiago Lima, A.J., Hoogeveen-Westerveld, M., Nakashima, A., Maat-Kievit, A., van den Ouweland, A., Halley, D., Kikkawa, U., and Nellist, M. (2014). Identification of Regions Critical for the Integrity of the TSC1-TSC2-TBC1D7 Complex. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093940"},{"key":"ref_57","unstructured":"(2024, February 04). GnomAD. Available online: https:\/\/gnomad.broadinstitute.org\/gene\/ENSG00000165699?dataset=gnomad_r4."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9909","DOI":"10.1038\/s41598-020-66588-4","article-title":"Mutational Analysis of TSC1 and TSC2 in Danish Patients with Tuberous Sclerosis Complex","volume":"10","author":"Rosengren","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/humu.22202","article-title":"Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex","volume":"34","author":"Ekong","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/s41431-021-00959-x","article-title":"The LOVD3 Platform: Efficient Genome-Wide Sharing of Genetic Variants","volume":"29","author":"Fokkema","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1007\/s00381-021-05059-1","article-title":"Identification of TSC2 Mosaic Mutation Limited to Cortical Tuber with TSC Targeted Sequencing: A Case Report and Literature Review","volume":"37","author":"Zhou","year":"2021","journal-title":"Childs. Nerv. Syst."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3389\/fgene.2020.00204","article-title":"Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study","volume":"11","author":"Ding","year":"2020","journal-title":"Front. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"16697","DOI":"10.1038\/s41598-017-16988-w","article-title":"Mutational Analysis of TSC1 and TSC2 Genes in Tuberous Sclerosis Complex Patients from Greece","volume":"7","author":"Avgeris","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/GIM.0b013e31803068c7","article-title":"Genotype\/Phenotype Correlation in 325 Individuals Referred for a Diagnosis of Tuberous Sclerosis Complex in the United States","volume":"9","author":"Au","year":"2007","journal-title":"Genet. Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Tyburczy, M.E., Dies, K.A., Glass, J., Camposano, S., Chekaluk, Y., Thorner, A.R., Lin, L., Krueger, D., Franz, D.N., and Thiele, E.A. (2015). Mosaic and Intronic Mutations in TSC1\/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005637"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"D\u2019Gama, A.M., and Poduri, A. (2023). Brain Somatic Mosaicism in Epilepsy: Bringing Results Back to the Clinic. Neurobiol. Dis., 181.","DOI":"10.1016\/j.nbd.2023.106104"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrg3424","article-title":"A Genomic View of Mosaicism and Human Disease","volume":"14","author":"Biesecker","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00401-019-02052-6","article-title":"Precise Detection of Low-Level Somatic Mutation in Resected Epilepsy Brain Tissue","volume":"138","author":"Sim","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_69","first-page":"119","article-title":"Disorders Caused by Genetic Mosaicism","volume":"116","author":"Moog","year":"2020","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s40246-021-00369-6","article-title":"Detection of Low-Level Parental Somatic Mosaicism for Clinically Relevant SNVs and Indels Identified in a Large Exome Sequencing Dataset","volume":"15","author":"Domogala","year":"2021","journal-title":"Hum. Genom."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1002\/ajmg.a.62389","article-title":"Genome Sequencing for Detection of Pathogenic Deep Intronic Variation: A Clinical Case Report Illustrating Opportunities and Challenges","volume":"185","author":"Walker","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/humu.24212","article-title":"Benchmarking Deep Learning Splice Prediction Tools Using Functional Splice Assays","volume":"42","author":"Riepe","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4899372","DOI":"10.1155\/2023\/4899372","article-title":"Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal","volume":"2023","author":"West","year":"2023","journal-title":"Hum. Mutat."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1136\/jmg-2023-109470","article-title":"Diagnostic Genome Sequencing Improves Diagnostic Yield: A Prospective Single-Centre Study in 1000 Patients with Inherited Eye Diseases","volume":"61","author":"Weisschuh","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/cge.14207","article-title":"Deep Intronic Variant in MVK as a Cause for Mevalonic Aciduria Initially Presenting as Non-Syndromic Retinitis Pigmentosa","volume":"102","author":"Dvaladze","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1167\/iovs.61.10.36","article-title":"Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants That Cause Retinal Dystrophies by Aberrant Exonization","volume":"61","author":"Tavares","year":"2020","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00439-010-0801-z","article-title":"Ultra Deep Sequencing Detects a Low Rate of Mosaic Mutations in Tuberous Sclerosis Complex","volume":"127","author":"Qin","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kwiatkowski, D.J., Whittemore, V.H., and Thiele, E.A. (2011). Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics, John Wiley & Sons.","DOI":"10.1002\/9783527630073"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/s41436-020-0823-4","article-title":"TSC2 Pathogenic Variants Are Predictive of Severe Clinical Manifestations in TSC Infants: Results of the EPISTOP Study","volume":"22","author":"Hamieh","year":"2020","journal-title":"Genet. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"omad029","DOI":"10.1093\/omcr\/omad029","article-title":"Late Diagnosis of Tuberous Sclerosis: A Case Report","volume":"2023","year":"2023","journal-title":"Oxf. Med. Case Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"806","DOI":"10.7326\/0003-4819-154-12-201106210-00008","article-title":"Recognition of Tuberous Sclerosis in Adult Women: Delayed Presentation with Life-Threatening Consequences","volume":"154","author":"Seibert","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/sj.ejhg.5201402","article-title":"Mutational Analysis of the TSC1 and TSC2 Genes in a Diagnostic Setting: Genotype--Phenotype Correlations and Comparison of Diagnostic DNA Techniques in Tuberous Sclerosis Complex","volume":"13","author":"Sancak","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6306","DOI":"10.1038\/sj.onc.1204009","article-title":"The Tuberous Sclerosis-1 (TSC1) Gene Product Hamartin Suppresses Cell Growth and Augments the Expression of the TSC2 Product Tuberin by Inhibiting Its Ubiquitination","volume":"19","author":"Benvenuto","year":"2000","journal-title":"Oncogene"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2329048X211012817","DOI":"10.1177\/2329048X211012817","article-title":"The Phenotypic Spectrum of Tuberous Sclerosis Complex: A Canadian Cohort","volume":"8","author":"Alsowat","year":"2021","journal-title":"Child. Neurol. Open"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/epi4.12286","article-title":"Epilepsy in Tuberous Sclerosis Complex: Findings from the TOSCA Study","volume":"4","author":"Nabbout","year":"2019","journal-title":"Epilepsia Open"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1136\/jmedgenet-2015-103154","article-title":"Intellectual Ability in Tuberous Sclerosis Complex Correlates with Predicted Effects of Mutations on TSC1 and TSC2 Proteins","volume":"52","author":"Wong","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1186\/s13023-023-02959-0","article-title":"A Single-Center Observational Study on Long-Term Neurodevelopmental Outcomes in Children with Tuberous Sclerosis Complex","volume":"18","author":"Mammadova","year":"2023","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.pediatrneurol.2019.03.003","article-title":"Tuberous Sclerosis Complex Genotypes and Developmental Phenotype","volume":"96","author":"Farach","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.spen.2015.10.002","article-title":"Genotype\/Phenotype Correlations in Tuberous Sclerosis Complex","volume":"22","author":"Curatolo","year":"2015","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1212\/WNL.0b013e3182104347","article-title":"Identification of Risk Factors for Autism Spectrum Disorders in Tuberous Sclerosis Complex","volume":"76","author":"Numis","year":"2011","journal-title":"Neurology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1111\/epi.12627","article-title":"Genotype\/Phenotype in Tuberous Sclerosis Complex: Associations with Clinical and Radiologic Manifestations","volume":"55","author":"Kothare","year":"2014","journal-title":"Epilepsia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1111\/epi.12680","article-title":"Severity of Manifestations in Tuberous Sclerosis Complex in Relation to Genotype","volume":"55","author":"Kothare","year":"2014","journal-title":"Epilepsia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/hmg\/ddq491","article-title":"Tsc2 Gene Inactivation Causes a More Severe Epilepsy Phenotype than Tsc1 Inactivation in a Mouse Model of Tuberous Sclerosis Complex","volume":"20","author":"Zeng","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1017\/cjn.2020.185","article-title":"Effect of Gene Mutation on Seizures in Surgery for Tuberous Sclerosis Complex","volume":"48","author":"Chivukula","year":"2021","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"917993","DOI":"10.3389\/fgene.2022.917993","article-title":"Spectrum of Germline and Somatic Mitochondrial DNA Variants in Tuberous Sclerosis Complex","volume":"13","author":"Giannikou","year":"2022","journal-title":"Front. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41439-022-00181-1","article-title":"Genotype-Phenotype Correlation of Renal Lesions in the Tuberous Sclerosis Complex","volume":"9","author":"Muto","year":"2022","journal-title":"Hum. Genome Var."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/ejhg.2011.241","article-title":"Genotype and Cognitive Phenotype of Patients with Tuberous Sclerosis Complex","volume":"20","author":"Black","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1055\/s-0040-1716495","article-title":"Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population","volume":"10","author":"Sudarshan","year":"2021","journal-title":"J. Pediatr. Genet."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6589","DOI":"10.1038\/s41598-020-62759-5","article-title":"First Comprehensive TSC1\/TSC2 Mutational Analysis in Mexican Patients with Tuberous Sclerosis Complex Reveals Numerous Novel Pathogenic Variants","volume":"10","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1038\/s41436-020-0915-1","article-title":"DYNC2H1 Hypomorphic or Retina-Predominant Variants Cause Nonsyndromic Retinal Degeneration","volume":"22","author":"Vig","year":"2020","journal-title":"Genet. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"104907","DOI":"10.1016\/j.ejmg.2023.104907","article-title":"Deep Intronic Variant Causes Aberrant Splicing of ATP7A in a Family with a Variable Occipital Horn Syndrome Phenotype","volume":"67","author":"Harkness","year":"2023","journal-title":"Eur. J. Med. Genet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00439-006-0308-9","article-title":"Identification of 54 Large Deletions\/Duplications in TSC1 and TSC2 Using MLPA, and Genotype-Phenotype Correlations","volume":"121","author":"Kozlowski","year":"2007","journal-title":"Hum. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ajhg.2023.04.002","article-title":"Comprehensive Genetic and Phenotype Analysis of 95 Individuals with Mosaic Tuberous Sclerosis Complex","volume":"110","author":"Klonowska","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1002\/humu.24454","article-title":"Mosaicism in Tuberous Sclerosis Complex: Lowering the Threshold for Clinical Reporting","volume":"43","author":"Ye","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1016\/j.celrep.2017.11.106","article-title":"Somatic Mutations Activating the MTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias","volume":"21","author":"Woodworth","year":"2017","journal-title":"Cell Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1172469","DOI":"10.3389\/fnins.2023.1172469","article-title":"The Human Brain through the Lens of Somatic Mosaicism","volume":"17","author":"Bizzotto","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1038\/s41436-019-0562-6","article-title":"Low-Level Mosaicism in Tuberous Sclerosis Complex: Prevalence, Clinical Features, and Risk of Disease Transmission","volume":"21","author":"Giannikou","year":"2019","journal-title":"Genet. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1038\/s41436-019-0520-3","article-title":"Phenotypic Distinctions between Mosaic Forms of Tuberous Sclerosis Complex","volume":"21","author":"Treichel","year":"2019","journal-title":"Genet. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1056\/NEJMoa0910752","article-title":"Timing of de Novo Mutagenesis\u2014A Twin Study of Sodium-Channel Mutations","volume":"363","author":"Vadlamudi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/ajmg.c.31656","article-title":"Minimal Mosaicism, Maximal Phenotype: Discordance between Clinical and Molecular Findings in Two Patients with Tuberous Sclerosis","volume":"178","author":"Byers","year":"2018","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ajhg.2017.01.030","article-title":"Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia","volume":"100","author":"Lim","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1177\/1550059417697841","article-title":"Childhood-Onset Epileptic Encephalopathy Associated With Isolated Focal Cortical Dysplasia and a Novel TSC1 Germline Mutation","volume":"49","author":"Hoelz","year":"2018","journal-title":"Clin. EEG Neurosci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00439-015-1611-0","article-title":"Detection of Low-Prevalence Somatic TSC2 Mutations in Sporadic Pulmonary Lymphangioleiomyomatosis Tissues by Deep Sequencing","volume":"135","author":"Fujita","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1159\/000513326","article-title":"Potential Pitfalls in Pre-Implantation Genetic Diagnosis in a Patient with Tuberous Sclerosis and Isolated Mosaicism for a TSC2 Variant in Renal Tissue","volume":"12","author":"Ikeda","year":"2021","journal-title":"Mol. Syndromol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"100180","DOI":"10.1016\/j.xjidi.2023.100180","article-title":"Diagnosis of Mosaic Tuberous Sclerosis Complex Using Next-Generation Sequencing of Subtle or Unusual Cutaneous Findings","volume":"3","author":"Treichel","year":"2023","journal-title":"JID Innov."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Chernoff, J. (2021). The Two-Hit Theory Hits 50. Mol. Biol. Cell, 32.","DOI":"10.1091\/mbc.E21-08-0407"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"15816","DOI":"10.1038\/ncomms15816","article-title":"The Genomic Landscape of Tuberous Sclerosis Complex","volume":"8","author":"Martin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13000-021-01138-8","article-title":"A Second Hit Somatic (p.R905W) and a Novel Germline Intron-Mutation of TSC2 Gene Is Found in Intestinal Lymphangioleiomyomatosis: A Case Report with Literature Review","volume":"16","author":"Han","year":"2021","journal-title":"Diagn. Pathol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1093\/hmg\/ddt597","article-title":"Sun Exposure Causes Somatic Second-Hit Mutations and Angiofibroma Development in Tuberous Sclerosis Complex","volume":"23","author":"Tyburczy","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1002\/ana.24368","article-title":"Familial Focal Epilepsy with Focal Cortical Dysplasia Due to DEPDC5 Mutations","volume":"77","author":"Baulac","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1001\/jamaneurol.2016.0363","article-title":"Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism","volume":"73","author":"Mirzaa","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1172\/JCI99384","article-title":"Second-Hit Mosaic Mutation in MTORC1 Repressor DEPDC5 Causes Focal Cortical Dysplasia-Associated Epilepsy","volume":"128","author":"Ribierre","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1002\/acn3.50815","article-title":"Second-Hit DEPDC5 Mutation Is Limited to Dysmorphic Neurons in Cortical Dysplasia Type IIA","volume":"6","author":"Lee","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e652","DOI":"10.1212\/NXG.0000000000000652","article-title":"Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy","volume":"8","author":"Bennett","year":"2022","journal-title":"Neurol. Genet."},{"key":"ref_127","first-page":"235","article-title":"A Diagnostic Algorithm for Enhanced Detection of Mosaic Tuberous Sclerosis Complex in Adults","volume":"182","author":"Treichel","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.jmoldx.2023.06.006","article-title":"An Integral Approach to the Molecular Diagnosis of Tuberous Sclerosis Complex: The Role of Mosaicism and Splicing Variants","volume":"25","author":"Tizzano","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Pel, J., Leung, A., Choi, W.W.Y., Despotovic, M., Ung, W.L., Shibahara, G., Gelinas, L., and Marziali, A. (2018). Rapid and Highly-Specific Generation of Targeted DNA Sequencing Libraries Enabled by Linking Capture Probes with Universal Primers. PLoS ONE, 13.","DOI":"10.1101\/422519"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Singh, R.R. (2022). Target Enrichment Approaches for Next-Generation Sequencing Applications in Oncology. Diagnostics, 12.","DOI":"10.3390\/diagnostics12071539"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13073-020-00791-w","article-title":"Best Practices for Variant Calling in Clinical Sequencing","volume":"12","author":"Koboldt","year":"2020","journal-title":"Genome Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.4103\/1673-5374.371356","article-title":"Utility of Droplet Digital Polymerase Chain Reaction for Studying Somatic Mosaicism: Brain Malformations and Beyond","volume":"18","author":"Lee","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1002\/ajmg.a.62433","article-title":"Low-Level Mosaicism in Tuberous Sclerosis Complex in Four Unrelated Patients: Comparison of Clinical Characteristics and Diagnostic Pathways","volume":"185","author":"Weis","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Nellist, M., Brouwer, R.W.W., Kockx, C.E.M., van Veghel-Plandsoen, M., Withagen-Hermans, C., Prins-Bakker, L., Hoogeveen-Westerveld, M., Mrsic, A., van den Berg, M.M.P., and Koopmans, A.E. (2015). Targeted Next Generation Sequencing Reveals Previously Unidentified TSC1 and TSC2 Mutations. BMC Med. Genet., 16.","DOI":"10.1186\/s12881-015-0155-4"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"fcaa235","DOI":"10.1093\/braincomms\/fcaa235","article-title":"Cerebrospinal Fluid Liquid Biopsy for Detecting Somatic Mosaicism in Brain","volume":"3","author":"Ye","year":"2021","journal-title":"Brain Commun."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1212\/WNL.0000000000201469","article-title":"Somatic Mosaic Pathogenic Variant Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes","volume":"99","author":"Ye","year":"2022","journal-title":"Neurology"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.pediatrneurol.2023.10.008","article-title":"Are Germline Mosaic TSC1\/2 Variants Present in Controls? Implications for Diagnosis","volume":"150","author":"Ye","year":"2024","journal-title":"Pediatr. Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1016\/j.gim.2022.07.020","article-title":"The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for Somatic Variants in AKT3, MTOR, PIK3CA, and PIK3R2","volume":"24","author":"Lai","year":"2022","journal-title":"Genet. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"e1802","DOI":"10.1002\/mgg3.1802","article-title":"Detection of TSC1\/TSC2 Mosaic Variants in Patients with Cardiac Rhabdomyoma and Tuberous Sclerosis Complex by Hybrid-Capture next-Generation Sequencing","volume":"9","author":"Wang","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13023-022-02266-0","article-title":"Perfect Match: MTOR Inhibitors and Tuberous Sclerosis Complex","volume":"17","author":"Luo","year":"2022","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1007\/s13311-021-01122-6","article-title":"Precision Therapy for Epilepsy Related to Brain Malformations","volume":"18","author":"Poduri","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_142","unstructured":"(2024, February 03). Clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05534672."},{"key":"ref_143","unstructured":"(2024, February 04). Clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05104983."},{"key":"ref_144","first-page":"TPS597","article-title":"Phase 2, Multicenter, Open-Label Basket Trial of Nab-Sirolimus for Patients with Malignant Solid Tumors Harboring Pathogenic Inactivating Alterations in TSC1 or TSC2 Genes (PRECISION I)","volume":"41","author":"Iyer","year":"2023","journal-title":"J. Clin. Orthod."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1111\/dmcn.14929","article-title":"Precision Therapy in the Genetic Epilepsies of Childhood","volume":"63","author":"Byrne","year":"2021","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.pediatrneurol.2019.06.018","article-title":"A Review of Investigations for Patients with Tuberous Sclerosis Complex Who Were Referred to the Tuberous Sclerosis Clinic at the Hospital for Sick Children: Identifying Gaps in Surveillance","volume":"102","author":"Alsowat","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pediatrneurol.2020.11.003","article-title":"Approach to Preventive Epilepsy Treatment in Tuberous Sclerosis Complex and Current Clinical Practice in 23 Countries","volume":"115","author":"Kotulska","year":"2021","journal-title":"Pediatr. Neurol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/epi4.12652","article-title":"The State of Pediatric Tuberous Sclerosis Complex Epilepsy Care: Results from a National Survey","volume":"7","author":"Whitney","year":"2022","journal-title":"Epilepsia Open"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/ana.25956","article-title":"Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial","volume":"89","author":"Kotulska","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/ana.26778","article-title":"Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial","volume":"95","author":"Bebin","year":"2023","journal-title":"Ann. Neurol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/uog.21880","article-title":"Fetal Tuberous Sclerosis and Diagnosis of Paternal Gonadal Mosaicism","volume":"55","author":"Tutschek","year":"2020","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"e21949","DOI":"10.1097\/MD.0000000000021949","article-title":"Fetal Cardiac Rhabdomyoma Due to Paternal Mosaicism of TSC2: A Case Report","volume":"99","author":"Chen","year":"2020","journal-title":"Medicine"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"g7611","DOI":"10.1136\/bmj.g7611","article-title":"Clinical Applications of Preimplantation Genetic Testing","volume":"350","author":"Brezina","year":"2015","journal-title":"BMJ"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/pd.4874","article-title":"The Impact of Mosaicism in Preimplantation Genetic Diagnosis (PGD): Approaches to PGD for Dominant Disorders in Couples without Family History","volume":"36","author":"Naja","year":"2016","journal-title":"Prenat. 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