{"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":1791477339004,"version":"4.3.4"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2015,11,5]],"date-time":"2015-11-05T00:00:00Z","timestamp":1446681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1005637","type":"journal-article","created":{"date-parts":[[2015,11,5]],"date-time":"2015-11-05T14:08:02Z","timestamp":1446732482000},"page":"e1005637","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":273,"title":["Mosaic and Intronic Mutations in TSC1\/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing"],"prefix":"10.1371","volume":"11","author":[{"given":"Magdalena E.","family":"Tyburczy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira A.","family":"Dies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Camposano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Chekaluk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron R.","family":"Thorner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darcy","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Franz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Thiele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kwiatkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,11,5]]},"reference":[{"key":"ref1","unstructured":"Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Numbers: 191100, 613254. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.omim.org\" xlink:type=\"simple\">http:\/\/www.omim.org<\/ext-link>."},{"issue":"13","key":"ref2","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"PB Crino","year":"2006","journal-title":"N Engl J Med"},{"key":"ref3","author":"DJ Kwiatkowski","year":"2010"},{"issue":"4","key":"ref4","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 Iinternational Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"H Northrup","year":"2013","journal-title":"Pediatr Neurol"},{"issue":"1","key":"ref5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1600-0404.2004.00366.x","article-title":"Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex","volume":"111","author":"M Ali","year":"2005","journal-title":"Acta Neurol Scand"},{"issue":"1","key":"ref6","first-page":"1","article-title":"Mutation analysis of TSC2 gene in 33 Turkish familial cases with tuberous sclerosis","volume":"45","author":"A Apak","year":"2003","journal-title":"Turk J Pediatr"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1086\/301705","article-title":"Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients","volume":"62","author":"S Au K-","year":"1998","journal-title":"Am J Hum Genet"},{"issue":"2","key":"ref8","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":"KS Au","year":"2007","journal-title":"Genet Med"},{"issue":"7","key":"ref9","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.braindev.2006.01.006","article-title":"Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex","volume":"28","author":"JE Choi","year":"2006","journal-title":"Brain Dev"},{"issue":"1","key":"ref10","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":"SL Dabora","year":"2001","journal-title":"Am J Hum Genet"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/1471-2350-7-72","article-title":"Molecular and clinical analyses of 84 patients with tuberous sclerosis complex","volume":"7","author":"CC Hung","year":"2006","journal-title":"BMC Med Genet"},{"issue":"7","key":"ref12","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00431-001-0903-7","article-title":"TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1\/ TSC2 frequency ratios","volume":"161","author":"N Langkau","year":"2002","journal-title":"Eur J Pediatr"},{"issue":"5","key":"ref13","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K","article-title":"Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis","volume":"14","author":"Y Niida","year":"1999","journal-title":"Hum Mutat"},{"issue":"4","key":"ref14","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":"ND Rendtorff","year":"2005","journal-title":"Hum Mutat"},{"issue":"6","key":"ref15","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\u2014phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex","volume":"13","author":"O Sancak","year":"2005","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"ref16","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1136\/jmg.36.4.285","article-title":"Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation","volume":"36","author":"M van Slegtenhorst","year":"1999","journal-title":"J Med Genet"},{"issue":"2","key":"ref17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/(SICI)1096-8628(20000117)90:2<123::AID-AJMG7>3.0.CO;2-L","article-title":"Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations","volume":"90","author":"Y Yamashita","year":"2000","journal-title":"Am J Med Genet"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","article-title":"16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16","volume":"75","author":"European Chromosome","year":"1993","journal-title":"Cell"},{"issue":"1","key":"ref19","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":"JR Sampson","year":"1989","journal-title":"J Med Genet"},{"issue":"5327","key":"ref20","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":"M van Slegtenhorst","year":"1997","journal-title":"Science"},{"issue":"2","key":"ref21","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":"SE Camposano","year":"2009","journal-title":"Ann Hum Genet"},{"issue":"2","key":"ref22","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/cge.12245","article-title":"Tuberous sclerosis complex without tubers and subependymal nodules: a phenotype-genotype study","volume":"86","author":"S Boronat","year":"2014","journal-title":"Clin Genet"},{"issue":"8","key":"ref23","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":"ME Tyburczy","year":"2014","journal-title":"Hum Mol Genet"},{"issue":"5","key":"ref24","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1086\/302381","article-title":"Comprehensive Mutation Analysis of TSC1 and TSC2-and Phenotypic Correlations in 150 Families with Tuberous Sclerosis","volume":"64","author":"AC Jones","year":"1999","journal-title":"Am J Hum Genet"},{"issue":"Pt 3","key":"ref25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1469-1809.1998.6230203.x","article-title":"A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients","volume":"62","author":"JM Young","year":"1998","journal-title":"Ann Hum Genet"},{"issue":"3","key":"ref26","first-page":"495","article-title":"Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences","volume":"1502","author":"K Mayer","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"ref27","unstructured":"Povey S, Ekong R. Tuberous sclerosis database. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/chromium.lovd.nl\/LOVD2\/TSC\" xlink:type=\"simple\">http:\/\/chromium.lovd.nl\/LOVD2\/TSC<\/ext-link>."},{"issue":"6","key":"ref28","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s00439-002-0821-4","article-title":"Nonsense-mediated RNA decay in the TSC1 gene suggests a useful tool pre- and post-positional cloning","volume":"111","author":"D Jeganathan","year":"2002","journal-title":"Hum Genet"},{"issue":"6","key":"ref29","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1007\/s00439-002-0830-3","article-title":"Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome","volume":"111","author":"K King","year":"2002","journal-title":"Hum Genet"},{"issue":"6686","key":"ref30","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/31508","article-title":"Association of missense and 5&apos;-splice-site mutations in tau with the inherited dementia FTDP-17","volume":"393","author":"M Hutton","year":"1998","journal-title":"Nature"},{"issue":"23","key":"ref31","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1093\/hmg\/10.23.2679","article-title":"A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees","volume":"10","author":"M Harland","year":"2001","journal-title":"Hum Mol Genet"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12881-015-0155-4","article-title":"Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations","volume":"16","author":"M Nellist","year":"2015","journal-title":"BMC Med Genet"},{"issue":"5","key":"ref33","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/(SICI)1098-1004(199911)14:5<401::AID-HUMU6>3.0.CO;2-R","article-title":"Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects","volume":"14","author":"K Mayer","year":"1999","journal-title":"Hum Mutat"},{"issue":"9","key":"ref34","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1056\/NEJM199903043400905","article-title":"Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis","volume":"340","author":"J Kwiatkowska","year":"1999","journal-title":"N Engl J Med"},{"issue":"4","key":"ref35","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1086\/302322","article-title":"Germ-Line Mosaicism in Tuberous Sclerosis: How Common?","volume":"64","author":"VM Rose","year":"1999","journal-title":"Am J Hum Genet"},{"issue":"4","key":"ref36","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1086\/514888","article-title":"Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene","volume":"61","author":"JR Sampson","year":"1997","journal-title":"Am J Hum Genet"},{"issue":"3","key":"ref37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/humu.8","article-title":"Low level mosaicism detectable by DHPLC but not by direct sequencing","volume":"17","author":"AC Jones","year":"2001","journal-title":"Hum Mutat"},{"issue":"2","key":"ref38","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/humu.10159","article-title":"Characterizing mutations in samples with low-level mosaicism by collection and analysis of DHPLC fractionated heteroduplexes","volume":"21","author":"P Emmerson","year":"2003","journal-title":"Hum Mutat"},{"issue":"6","key":"ref39","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1086\/302412","article-title":"High rate of mosaicism in tuberous sclerosis complex","volume":"64","author":"S Verhoef","year":"1999","journal-title":"Am J Hum Genet"},{"issue":"13","key":"ref40","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/hmg\/6.13.2265","article-title":"Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis","volume":"6","author":"JR Yates","year":"1997","journal-title":"Hum Mol Genet"},{"issue":"3\u20134","key":"ref41","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":"P Kozlowski","year":"2007","journal-title":"Hum Genet"},{"issue":"8943","key":"ref42","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/S0140-6736(95)90213-9","article-title":"Somatic mosaicism and clinical variation in tuberous sclerosis complex","volume":"345","author":"S Verhoef","year":"1995","journal-title":"Lancet"},{"issue":"5","key":"ref43","doi-asserted-by":"crossref","first-page":"e69","DOI":"10.1136\/jmg.2003.014126","article-title":"Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis","volume":"41","author":"PS Roberts","year":"2004","journal-title":"J Med Genet"},{"issue":"Pt 3","key":"ref44","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1042\/bst0310592","article-title":"TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis","volume":"31","author":"JR Sampson","year":"2003","journal-title":"Biochem Soc Trans"},{"issue":"5","key":"ref45","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":"W Qin","year":"2010","journal-title":"Hum Genet"},{"issue":"7","key":"ref46","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1136\/jmg.2006.047753","article-title":"Mosaicism in neurofibromatosis type 2: an update of risk based on uni\/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification","volume":"44","author":"DG Evans","year":"2007","journal-title":"J Med Genet"},{"issue":"2","key":"ref47","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1136\/jmg.40.2.109","article-title":"Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas","volume":"40","author":"L Kluwe","year":"2003","journal-title":"J Med Genet"},{"issue":"6","key":"ref48","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1136\/jmg.35.6.450","article-title":"Genotype\/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations","volume":"35","author":"DG Evans","year":"1998","journal-title":"J Med Genet"},{"issue":"7","key":"ref49","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1093\/hmg\/ddu597","article-title":"A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex","volume":"24","author":"ME Tyburczy","year":"2015","journal-title":"Hum Mol Genet"},{"issue":"5","key":"ref50","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"H Li","year":"2010","journal-title":"Bioinformatics"},{"issue":"9","key":"ref51","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":"A McKenna","year":"2010","journal-title":"Genome Res"},{"issue":"16","key":"ref52","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"1","key":"ref53","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"JT Robinson","year":"2011","journal-title":"Nat Biotechnol"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"GR Abecasis","year":"2012","journal-title":"Nature"},{"key":"ref55","unstructured":"Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/evs.gs.washington.edu\/EVS\/\" xlink:type=\"simple\">http:\/\/evs.gs.washington.edu\/EVS\/<\/ext-link>."},{"key":"ref56","unstructured":"Exome Aggregation Consortium (ExAC), Cambridge, MA. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/exac.broadinstitute.org\/\" xlink:type=\"simple\">http:\/\/exac.broadinstitute.org\/<\/ext-link>."},{"issue":"4","key":"ref57","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":"IA Adzhubei","year":"2010","journal-title":"Nat Methods"},{"issue":"4","key":"ref58","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":"IA Adzhubei","year":"2010","journal-title":"Nat Methods"},{"issue":"5","key":"ref59","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1101\/gr.176601","article-title":"Predicting deleterious amino acid substitutions","volume":"11","author":"PC Ng","year":"2001","journal-title":"Genome Res"},{"issue":"7","key":"ref60","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":"P Kumar","year":"2009","journal-title":"Nat Protoc"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1005637","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T03:46:30Z","timestamp":1718163990000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1005637"}},"subtitle":[],"editor":[{"given":"Bruce R.","family":"Korf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,11,5]]},"references-count":60,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2015,11,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1005637","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,5]]}}}