{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:17:46Z","timestamp":1791285466041,"version":"4.1.0"},"reference-count":63,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,3]],"date-time":"2024-11-03T00:00:00Z","timestamp":1730592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["2011\/14329-9"],"award-info":[{"award-number":["2011\/14329-9"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["2017\/06100-8"],"award-info":[{"award-number":["2017\/06100-8"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["2019\/10868-4"],"award-info":[{"award-number":["2019\/10868-4"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["CAPES-PROEX\/001"],"award-info":[{"award-number":["CAPES-PROEX\/001"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["CAPES 1570747"],"award-info":[{"award-number":["CAPES 1570747"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["CAPES-DSE 88881.132401\/2016-01"],"award-info":[{"award-number":["CAPES-DSE 88881.132401\/2016-01"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["06-16"],"award-info":[{"award-number":["06-16"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["2016-P07"],"award-info":[{"award-number":["2016-P07"]}]},{"name":"S\u00e3o Paulo Research Foundation\/FAPESP","award":["20380009\/2024"],"award-info":[{"award-number":["20380009\/2024"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["2011\/14329-9"],"award-info":[{"award-number":["2011\/14329-9"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["2017\/06100-8"],"award-info":[{"award-number":["2017\/06100-8"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["2019\/10868-4"],"award-info":[{"award-number":["2019\/10868-4"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["CAPES-PROEX\/001"],"award-info":[{"award-number":["CAPES-PROEX\/001"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["CAPES 1570747"],"award-info":[{"award-number":["CAPES 1570747"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["CAPES-DSE 88881.132401\/2016-01"],"award-info":[{"award-number":["CAPES-DSE 88881.132401\/2016-01"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["06-16"],"award-info":[{"award-number":["06-16"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["2016-P07"],"award-info":[{"award-number":["2016-P07"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Bras\u00edlia, Brazil) fellowships","award":["20380009\/2024"],"award-info":[{"award-number":["20380009\/2024"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["2011\/14329-9"],"award-info":[{"award-number":["2011\/14329-9"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["2017\/06100-8"],"award-info":[{"award-number":["2017\/06100-8"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["2019\/10868-4"],"award-info":[{"award-number":["2019\/10868-4"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["CAPES-PROEX\/001"],"award-info":[{"award-number":["CAPES-PROEX\/001"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["CAPES 1570747"],"award-info":[{"award-number":["CAPES 1570747"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["CAPES-DSE 88881.132401\/2016-01"],"award-info":[{"award-number":["CAPES-DSE 88881.132401\/2016-01"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["06-16"],"award-info":[{"award-number":["06-16"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["2016-P07"],"award-info":[{"award-number":["2016-P07"]}]},{"name":"Michelle Foundation (The Netherlands)","award":["20380009\/2024"],"award-info":[{"award-number":["20380009\/2024"]}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["2011\/14329-9"],"award-info":[{"award-number":["2011\/14329-9"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["2017\/06100-8"],"award-info":[{"award-number":["2017\/06100-8"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["2019\/10868-4"],"award-info":[{"award-number":["2019\/10868-4"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["CAPES-PROEX\/001"],"award-info":[{"award-number":["CAPES-PROEX\/001"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["CAPES 1570747"],"award-info":[{"award-number":["CAPES 1570747"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["CAPES-DSE 88881.132401\/2016-01"],"award-info":[{"award-number":["CAPES-DSE 88881.132401\/2016-01"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["06-16"],"award-info":[{"award-number":["06-16"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["2016-P07"],"award-info":[{"award-number":["2016-P07"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"TS Alliance","doi-asserted-by":"publisher","award":["20380009\/2024"],"award-info":[{"award-number":["20380009\/2024"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["2011\/14329-9"],"award-info":[{"award-number":["2011\/14329-9"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["2017\/06100-8"],"award-info":[{"award-number":["2017\/06100-8"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["2019\/10868-4"],"award-info":[{"award-number":["2019\/10868-4"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["CAPES-PROEX\/001"],"award-info":[{"award-number":["CAPES-PROEX\/001"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["CAPES 1570747"],"award-info":[{"award-number":["CAPES 1570747"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["CAPES-DSE 88881.132401\/2016-01"],"award-info":[{"award-number":["CAPES-DSE 88881.132401\/2016-01"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["06-16"],"award-info":[{"award-number":["06-16"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["2016-P07"],"award-info":[{"award-number":["2016-P07"]}]},{"name":"Brazil Ministry of Education Process, Bras\u00edlia DF, Brazil","award":["20380009\/2024"],"award-info":[{"award-number":["20380009\/2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. TSC1 and TSC2 encode the core components of the TSC1\/2 complex (TSC1\/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of TSC1 and TSC2 variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to TSC1 and TSC2 in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2. Of these, 35 were novel. Disruption of TSC1\/2 activity was demonstrated for seven TSC2 variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis.<\/jats:p>","DOI":"10.3390\/genes15111432","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T03:57:34Z","timestamp":1730692654000},"page":"1432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0831-0380","authenticated-orcid":false,"given":"Luiz Gustavo","family":"Dufner-Almeida","sequence":"first","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"},{"name":"Department of Clinical Genetics, Erasmus Medical Center, 3015 Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8674-4152","authenticated-orcid":false,"given":"La\u00eds F. M.","family":"Cardozo","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Center, Department of Pediatrics, Hospital de Cl\u00ednicas, Universidade Federal do Paran\u00e1, Curitiba 80060-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana R.","family":"Schwind","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Center, Department of Pediatrics, Hospital de Cl\u00ednicas, Universidade Federal do Paran\u00e1, Curitiba 80060-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielly","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Center, Department of Pediatrics, Hospital de Cl\u00ednicas, Universidade Federal do Paran\u00e1, Curitiba 80060-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5692-5577","authenticated-orcid":false,"given":"Juliana Paula G.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Santa Casa de Miseric\u00f3rdia, S\u00e3o Paulo 01221-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Maria","family":"Cappellano","sequence":"additional","affiliation":[{"name":"Grupo de Apoio ao Adolescente e \u00e0 Crian\u00e7a com C\u00e2ncer, Instituto de Oncologia Pedi\u00e1trica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-001, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago G. P.","family":"Alegria","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santoesha","family":"Nanhoe","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, 3015 Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, 3015 Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Passos-Bueno","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9511-653X","authenticated-orcid":false,"given":"Silvana","family":"Chiavegatto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"},{"name":"Department of Psychiatry, Instituto de Psiquiatria, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05403-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasjla S.","family":"Silva","sequence":"additional","affiliation":[{"name":"Grupo de Apoio ao Adolescente e \u00e0 Crian\u00e7a com C\u00e2ncer, Instituto de Oncologia Pedi\u00e1trica, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-001, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio","family":"Rosemberg","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Santa Casa de Miseric\u00f3rdia, S\u00e3o Paulo 01221-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula A.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Psychology, Universidade Federal do Paran\u00e1, Curitiba 80060-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio Ant\u00f4nio","family":"Antoniuk","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Center, Department of Pediatrics, Hospital de Cl\u00ednicas, Universidade Federal do Paran\u00e1, Curitiba 80060-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana A.","family":"Haddad","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","article-title":"Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"Northrup","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2021.07.011","article-title":"Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations","volume":"123","author":"Northrup","year":"2021","journal-title":"Pediatr. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1136\/jmg.26.1.28","article-title":"Genetic aspects of tuberous sclerosis in the west of Scotland","volume":"26","author":"Sampson","year":"1989","journal-title":"J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/S0140-6736(05)78872-3","article-title":"Prevalence of tuberous sclerosis estimated by capture-recapture analysis","volume":"351","author":"Shiell","year":"1998","journal-title":"Lancet"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","unstructured":"European Chromosome 16 Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75, 1305\u20131315.","DOI":"10.1016\/0092-8674(93)90618-Z"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.molcel.2012.06.009","article-title":"TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1","volume":"47","author":"Dibble","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/ncb2763","article-title":"Signal integration by mTORC1 coordinates nutrient input with biosynthetic output","volume":"15","author":"Dibble","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.celrep.2017.10.029","article-title":"The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels","volume":"21","author":"Hoxhaj","year":"2017","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1177\/088307389801301206","article-title":"Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria","volume":"13","author":"Roach","year":"1998","journal-title":"J. Child Neurol."},{"key":"ref_12","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. Part C Semin. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/j.1469-1809.2008.00496.x","article-title":"Distinct clinical characteristics of tuberous sclerosis complex patients with no mutation identified","volume":"73","author":"Camposano","year":"2009","journal-title":"Ann. Hum. Genet."},{"key":"ref_14","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_15","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_16","first-page":"20232029","article-title":"Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex","volume":"23","author":"Tyburczy","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nellist, M., Brouwer, R.W., Kockx, C.E., van Veghel-Plandsoen, M., Withagen-Hermans, C., Prins-Bakker, L., Hoogeveen-Westerveld, M., Mrsic, A., van den Berg, M.M., 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_18","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_19","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_20","unstructured":"Krawetz, S., and Misener, S. (2000). Primer3 on the WWW for general users and for biologist programmers. Bioinformatics Methods and Protocols: Methods in Molecular Biology, Humana Press."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1101\/gr.6339607","article-title":"What is a gene, post-ENCODE? History and updated definition","volume":"17","author":"Gerstein","year":"2007","journal-title":"Genome Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1038\/nprot.2008.112","article-title":"PCR-amplification of GC-rich regions: \u2018Slowdown PCR\u2019","volume":"3","author":"Frey","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, H., and Durbin, R. (2009). Fast and accurate short read alignment with Burrows\u2014Wheeler Transform. Bioinformatics. Bioinformatics, 25.","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/humu.20227","article-title":"Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1\/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations","volume":"26","author":"Rendtorff","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1007\/s12098-011-0408-y","article-title":"Tuberous sclerosis: Diagnosis and prenatal diagnosis by MLPA","volume":"79","author":"Dalal","year":"2012","journal-title":"Indian J. Pediatr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/ejhg.2011.60","article-title":"Multiplex ligation-depending probe amplification is not suitable for detection of low-grade mosaicism","volume":"19","author":"Wouters","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1601-183X.2008.00458.x","article-title":"Anabolic\u2014androgenic steroid treatment induces behavioral disinhibition and downregulation of serotonin receptor messenger RNA in the prefrontal cortex and amygdala of male mice","volume":"8","author":"Ambar","year":"2009","journal-title":"Genes. Brain Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/humu.23348","article-title":"VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions","volume":"39","author":"Freeman","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/humu.20654","article-title":"Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker","volume":"29","author":"Wildeman","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_32","first-page":"405","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. Off. J. Am. Coll. Med. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D754","DOI":"10.1093\/nar\/gkx1098","article-title":"Ensembl 2018","volume":"46","author":"Zerbino","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1146\/annurev.genom.7.080505.115630","article-title":"Predicting the effects of amino acid substitutions on protein function","volume":"7","author":"Ng","year":"2006","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: Mutations, PTMs and recalibrations","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/humu.21609","article-title":"SpliceAid 2: A database of human splicing factors expression data and RNA target motifs","volume":"33","author":"Piva","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human Splicing Finder: An online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature02505","article-title":"The GTPase-activating protein Rap1GAP uses a catalytic asparagine","volume":"429","author":"Daumke","year":"2004","journal-title":"Nature"},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1002\/humu.21451","article-title":"Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex","volume":"32","author":"Wentink","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_46","first-page":"759","article-title":"Comparison of the functional and structural characteristics of rare TSC2 variants with clinical and genetic findings","volume":"41","author":"Nanhoe","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1038\/ejhg.2016.85","article-title":"Genotype and brain pathology phenotype in children with tuberous sclerosis complex","volume":"24","author":"Overwater","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_48","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":"Tenes","year":"2023","journal-title":"J. Mol. Diagn."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/sj.ejhg.5201276","article-title":"Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex","volume":"13","author":"Nellist","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/ejhg.2015.47","article-title":"Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2","volume":"23","author":"Kwiatkowski","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1086\/302381","article-title":"Comprehensive mutation analysis of TSC1 and TSC2\u2014and phenotypic correlations in 150 families with tuberous sclerosis","volume":"64","author":"Jones","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1086\/316951","article-title":"Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs","volume":"68","author":"Dabora","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_53","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\u2013phenotype 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_54","doi-asserted-by":"crossref","unstructured":"Hung, C.C., Su, Y.N., Chien, S.C., Liou, H.H., Chen, C.C., Chen, P.C., Hsieh, C.J., Chen, C.P., Lee, W.T., and Lin, W.L. (2006). Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med. Genet., 7.","DOI":"10.1186\/1471-2350-7-72"},{"key":"ref_55","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_56","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_57","doi-asserted-by":"crossref","unstructured":"Rosset, C., Vairo, F., Bandeira, I.C., Correia, R.L., de Goes, F.V., da Silva, R.T.B., Bueno, L.S.M., de Miranda Gomes, M.C.S., Galvao, H.C.R., and Neri, J. (2017). Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185713"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Nunes, B.A., Romano, A., Pasa Morgan, M.A., Goncalves, A.A., Cardozo, L.F.M., de Almeida, L.G.D., Haddad, L.A., Crippa, A.C.S., Antoniuk, S.A., and Abagge, K.T. (2024). A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC). An. Bras. Dermatol.","DOI":"10.1016\/j.abd.2023.11.004"},{"key":"ref_59","first-page":"s00441787797","article-title":"Neuropsychological profile in tuberous sclerosis complex: A study of clinical and cognitive variables in a cohort from Brazil","volume":"82","author":"Cardozo","year":"2024","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/humu.22007","article-title":"Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex","volume":"33","author":"Ekong","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/gcc.20733","article-title":"Large intragenic deletions of the NF2 gene: Breakpoints and associated phenotypes","volume":"49","author":"Kutsche","year":"2010","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/humu.10254","article-title":"Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs","volume":"22","author":"Abeysinghe","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.1093\/hmg\/ddv146","article-title":"Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3","volume":"24","author":"Gu","year":"2015","journal-title":"Hum. Mol. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1432\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:27:31Z","timestamp":1760113651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,3]]},"references-count":63,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["genes15111432"],"URL":"https:\/\/doi.org\/10.3390\/genes15111432","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,3]]}}}