{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:35:37Z","timestamp":1791477337292,"version":"4.3.4"},"reference-count":33,"publisher":"Elsevier BV","issue":"9","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T00:00:00Z","timestamp":1725148800000},"content-version":"vor","delay-in-days":366,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100005262","name":"Ministry of Advanced Education and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005262","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","jmdjournal.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Molecular Diagnostics"],"published-print":{"date-parts":[[2023,9]]},"DOI":"10.1016\/j.jmoldx.2023.06.006","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T19:23:36Z","timestamp":1687634616000},"page":"692-701","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"title":["An Integral Approach to the Molecular Diagnosis of Tuberous Sclerosis Complex"],"prefix":"10.1016","volume":"25","author":[{"given":"Laura","family":"Blasco-P\u00e9rez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Iranzo-Nuez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4604-7862","authenticated-orcid":false,"given":"Ricard","family":"L\u00f3pez-Ortega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9406-5352","authenticated-orcid":false,"given":"Desir\u00e9e","family":"Mart\u00ednez-Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-3238","authenticated-orcid":false,"given":"Mar\u00eda","family":"Camprodon-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ten\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5623-6862","authenticated-orcid":false,"given":"Mar\u00eda","family":"Antol\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo F.","family":"Tizzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0096-3336","authenticated-orcid":false,"given":"Elena","family":"Garc\u00eda-Arum\u00ed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jmoldx.2023.06.006_bib1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1749-6632.1991.tb37754.x","article-title":"Epidemiology of tuberous sclerosis","volume":"615","author":"Osborne","year":"1991","journal-title":"Ann N Y Acad Sci"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1136\/jmg.30.1.41","article-title":"Variability of expression in tuberous sclerosis","volume":"30","author":"Northrup","year":"1993","journal-title":"J Med Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib3","series-title":"GeneReviews [Internet]","article-title":"Tuberous sclerosis complex","author":"Northrup","year":"1993"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib4","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":"10.1016\/j.jmoldx.2023.06.006_bib5","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":"10.1016\/j.jmoldx.2023.06.006_bib6","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","article-title":"Identification and characterization of the tuberous sclerosis gene on chromosome 16","volume":"75","year":"1993","journal-title":"Cell"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib7","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":"Van Slegtenhorst","year":"1997","journal-title":"Science"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib8","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1093\/hmg\/7.6.1053","article-title":"Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products","volume":"7","author":"Van Slegtenhorst","year":"1998","journal-title":"Hum Mol Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib9","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":"10.1016\/j.jmoldx.2023.06.006_bib10","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib11","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":"10.1016\/j.jmoldx.2023.06.006_bib12","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/humu.21438","article-title":"LOVD v.2.0: the next generation in gene variant databases","volume":"32","author":"Fokkema","year":"2011","journal-title":"Hum Mutat"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12881-015-0155-4","article-title":"Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 and mutations","volume":"16","author":"Nellist","year":"2015","journal-title":"BMC Med Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005637","article-title":"Mosaic and intronic mutations in TSC1\/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing","volume":"11","author":"Tyburczy","year":"2015","journal-title":"PLoS Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib15","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":"10.1016\/j.jmoldx.2023.06.006_bib16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet Med"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib17","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1136\/jmedgenet-2020-107604","article-title":"A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome","volume":"59","author":"Fern\u00e1ndez-\u00c1lvarez","year":"2022","journal-title":"J Med Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib18","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1093\/nar\/15.17.7155","article-title":"RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression","volume":"15","author":"Shapiro","year":"1987","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib19","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J Comput Biol"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib20","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":"10.1016\/j.jmoldx.2023.06.006_bib21","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":"Hoogeveen-Westerveld","year":"2012","journal-title":"Hum Mutat"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib22","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0092-8674(01)00333-6","article-title":"Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size","volume":"105","author":"Potter","year":"2001","journal-title":"Cell"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib23","doi-asserted-by":"crossref","first-page":"1","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":"10.1016\/j.jmoldx.2023.06.006_bib24","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":"Hoogeveen-Westerveld","year":"2013","journal-title":"Hum Mutat"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/hmg\/5.2.249","article-title":"Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients","volume":"5","author":"Wilson","year":"1996","journal-title":"Hum Mol Genet"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib26","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1177\/08830738040190020401","article-title":"Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis","volume":"19","author":"J\u00f3\u017awiak","year":"2004","journal-title":"J Child Neurol"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib27","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":"10.1016\/j.jmoldx.2023.06.006_bib28","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":"10.1016\/j.jmoldx.2023.06.006_bib29","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":"10.1016\/j.jmoldx.2023.06.006_bib30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib31","doi-asserted-by":"crossref","first-page":"1","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","author":"Reyna-Fabi\u00e1n","year":"2020","journal-title":"Sci Rep"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib32","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.clineuro.2017.01.015","article-title":"Novel TSC1 and TSC2 gene mutations in Chinese patients with tuberous sclerosis complex","volume":"154","author":"Yu","year":"2017","journal-title":"Clin Neurol Neurosurg"},{"key":"10.1016\/j.jmoldx.2023.06.006_bib33","doi-asserted-by":"crossref","DOI":"10.3390\/ijms231911175","article-title":"Genotype and phenotype landscape of 283 Japanese patients with tuberous sclerosis complex","volume":"23","author":"Togi","year":"2022","journal-title":"Int J Mol Sci"}],"container-title":["The Journal of Molecular Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525157823001344?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525157823001344?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T18:17:55Z","timestamp":1761502675000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1525157823001344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["S1525157823001344"],"URL":"https:\/\/doi.org\/10.1016\/j.jmoldx.2023.06.006","relation":{},"ISSN":["1525-1578"],"issn-type":[{"value":"1525-1578","type":"print"}],"subject":[],"published":{"date-parts":[[2023,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"An Integral Approach to the Molecular Diagnosis of Tuberous Sclerosis Complex","name":"articletitle","label":"Article Title"},{"value":"The Journal of Molecular Diagnostics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jmoldx.2023.06.006","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}