{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:48:04Z","timestamp":1783014484584,"version":"3.54.6"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["22K07854"],"award-info":[{"award-number":["22K07854"]}]},{"name":"The Tokumori Yasumoto Memorial Trust for Researches on TSC and Related Rare Neurological","award":["22K07854"],"award-info":[{"award-number":["22K07854"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss of function mutations in either TSC1 or TSC2. Genotype and phenotype analyses are conducted worldwide, but there have been few large-scale studies on Japanese patients, and there are still many unclear points. This study analyzed 283 Japanese patients with TSC (225 definite, 53 possible, and 5 genetic diagnoses). A total of 200 mutations (64 TSC1, 136 TSC2) were identified, of which 17 were mosaic mutations, 11 were large intragenic deletions, and four were splicing abnormalities due to deep intronic mutations. Several lesions and symptoms differed in prevalence and severity between TSC1 and TSC2 patients and were generally more severe in TSC2 patients. Moreover, TSC2 missense and in-frame mutations may attenuate skin and renal symptoms compared to other TSC2 mutations. Genetic testing revealed that approximately 20% of parents of a proband had mild TSC, which could have been missed. The patient demographics presented in this study revealed a high frequency of TSC1 patients and a low prevalence of epilepsy compared to global statistics. More patients with mild neuropsychiatric phenotypes were diagnosed in Japan, seemingly due to a higher utilization of brain imaging, and suggesting the possibility that a significant amount of mild TSC patients may not be correctly diagnosed worldwide.<\/jats:p>","DOI":"10.3390\/ijms231911175","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T21:10:05Z","timestamp":1663881005000},"page":"11175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3189-8111","authenticated-orcid":false,"given":"Sumihito","family":"Togi","sequence":"first","affiliation":[{"name":"Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan"},{"name":"Department of Advanced Medicine, Division of Genomic Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7600-3481","authenticated-orcid":false,"given":"Hiroki","family":"Ura","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan"},{"name":"Department of Advanced Medicine, Division of Genomic Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisayo","family":"Hatanaka","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-7962","authenticated-orcid":false,"given":"Yo","family":"Niida","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Japan"},{"name":"Department of Advanced Medicine, Division of Genomic Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","unstructured":"Gomez, M.R., Sampson, J.R., and Whittemore, V.H. (1999). Tuberous Sclerosis Complex, Oxford University Press. [3rd ed.].","DOI":"10.1093\/oso\/9780195122107.001.0001"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.pediatrneurol.2003.09.002","article-title":"Tuberous sclerosis complex: Genetics to pathogenesis","volume":"29","author":"Narayanan","year":"2003","journal-title":"Pediatr. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0140-6736(08)61279-9","article-title":"Tuberous sclerosis","volume":"372","author":"Curatolo","year":"2008","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S1474-4422(15)00069-1","article-title":"Neurological and neuropsychiatric aspects of tuberous sclerosis complex","volume":"14","author":"Curatolo","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","unstructured":"(1993). The European Chromosome 16 Tuberous Sclerosis Consortium 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_8","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S1470-2045(07)70411-4","article-title":"Possible mechanisms of disease development in tuberous sclerosis","volume":"9","author":"Jozwiak","year":"2008","journal-title":"Lancet. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.4161\/cbt.2.5.446","article-title":"Rhebbing up mTOR: New insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis","volume":"2","author":"Kwiatkowski","year":"2003","journal-title":"Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_11","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":"Niida","year":"1999","journal-title":"Hum. Mutat."},{"key":"ref_12","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_13","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_14","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1136\/jmg.38.5.347","article-title":"A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex","volume":"38","author":"Khare","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/ana.21037","article-title":"Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation","volume":"60","author":"Jansen","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/ng1294-328","article-title":"Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease\u2014A contiguous gene syndrome","volume":"8","author":"Peral","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13023-016-0553-5","article-title":"TuberOus SClerosis registry to increase disease Awareness (TOSCA)\u2014Baseline data on 2093 patients","volume":"12","author":"Kingswood","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/jhg.2013.3","article-title":"Mutational analysis of TSC1 and TSC2 in Japanese patients with tuberous sclerosis complex revealed higher incidence of TSC1 patients than previously reported","volume":"58","author":"Niida","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.jmoldx.2020.12.009","article-title":"Optimization and Validation of Multimodular, Long-Range PCR-Based Next-Generation Sequencing Assays for Comprehensive Detection of Mutation in Tuberous Sclerosis Complex","volume":"23","author":"Togi","year":"2021","journal-title":"J. Mol. Diagn."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Togi, S., Ura, H., and Niida, Y. (2021). Application of Combined Long Amplicon Sequencing (CoLAS) for Genetic Analysis of Neurofibromatosis Type 1: A Pilot Study. Curr. Issues Mol. Biol., 43.","DOI":"10.3390\/cimb43020057"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wataya-Kaneda, M., Tanaka, M., Hamasaki, T., and Katayama, I. (2013). Trends in the prevalence of tuberous sclerosis complex manifestations: An epidemiological study of 166 Japanese patients. PLoS ONE, 8.","DOI":"10.1371\/annotation\/c511ee3c-f91a-4cfe-bad7-6ef58579717e"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1093\/ndt\/gfy063","article-title":"Renal angiomyolipoma in patients with tuberous sclerosis complex: Findings from the TuberOus SClerosis registry to increase disease Awareness","volume":"34","author":"Kingswood","year":"2019","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_23","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_24","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":"Jones","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","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_26","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_27","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_28","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/S1525-1578(10)60586-7","article-title":"A case of solitary subependymal giant cell astrocytoma: Two somatic hits of TSC2 in the tumor, without evidence of somatic mosaicism","volume":"7","author":"Ichikawa","year":"2005","journal-title":"J. Mol. Diagn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00381-021-05399-y","article-title":"TSC2 somatic mosaic mutation, including extra-tumor tissue, may be the developmental cause of solitary subependymal giant cell astrocytoma","volume":"38","author":"Sasaki","year":"2022","journal-title":"Childs Nerv. Syst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e001493","DOI":"10.1161\/JAHA.114.001493","article-title":"Cardiovascular manifestations of tuberous sclerosis complex and summary of the revised diagnostic criteria and surveillance and management recommendations from the International Tuberous Sclerosis Consensus Group","volume":"3","author":"Hinton","year":"2014","journal-title":"J. Am. Heart. Assoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.legalmed.2018.10.001","article-title":"Autopsy case of right ventricular rhabdomyoma in tuberous sclerosis complex","volume":"36","author":"Kondo","year":"2019","journal-title":"Leg. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.pediatrneurol.2015.01.004","article-title":"Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex","volume":"52","author":"Goyer","year":"2015","journal-title":"Pediatr. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e1199","DOI":"10.1542\/peds.2013-3293","article-title":"Rapid regression of left ventricular outflow tract rhabdomyoma after sirolimus therapy","volume":"134","author":"Breathnach","year":"2014","journal-title":"Pediatrics"},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s11604-008-0259-2","article-title":"Radiologist supply and workload: International comparison\u2014Working Group of Japanese College of Radiology","volume":"26","author":"Nakajima","year":"2008","journal-title":"Radiat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1086\/321972","article-title":"Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions","volume":"69","author":"Niida","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1073\/pnas.97.11.6085","article-title":"Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis","volume":"97","author":"Carsillo","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shoji, T., Konno, S., Niida, Y., Ogi, T., Suzuki, M., Shimizu, K., Hida, Y., Kaga, K., Seyama, K., and Naka, T. (2019). Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212370"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sudarshan, S., Kumar, M., Kaur, P., Kumar, A.G.S., Sapra, S., Gulati, S., Gupta, N., Kabra, M., and Chowdhury, M.R. (2019). Decoding of novel missense TSC2 gene variants using in-silico methods. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0891-y"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41467-020-20522-4","article-title":"Structural insights into TSC complex assembly and GAP activity on Rheb","volume":"12","author":"Yang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_41","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_42","first-page":"101526","article-title":"Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex","volume":"34","author":"Shoji","year":"2021","journal-title":"Respir. Med. Case. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/cia2.12128","article-title":"Squamous cell carcinoma\u2013like ungual fibroma as early diagnostic indicators of tuberous sclerosis complex in an elderly patient","volume":"3","author":"Yokoyama","year":"2020","journal-title":"J. Cutan. Immunol. Allergy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/ndt\/12.9.1900","article-title":"A large TSC2 and PKD1 gene deletion is associated with renal and extrarenal signs of autosomal dominant polycystic kidney disease","volume":"12","author":"Longa","year":"1997","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/jjco\/hyu024","article-title":"Two novel gross deletions of TSC2 in Malaysian patients with tuberous sclerosis complex and TSC2\/PKD1 contiguous deletion syndrome","volume":"44","author":"Ismail","year":"2014","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1097\/DAD.0b013e3181970e44","article-title":"TSC2\/PKD1 contiguous gene syndrome: A report of 2 cases with emphasis on dermatopathologic findings","volume":"31","author":"Kacerovska","year":"2009","journal-title":"Am. J. Derm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.seizure.2021.01.016","article-title":"Infantile spasms and early-onset progressive polycystic renal lesions associated with TSC2\/PKD1 contiguous gene deletion syndrome","volume":"86","author":"Matsubara","year":"2021","journal-title":"Seizure"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.ymgme.2012.09.008","article-title":"Applying and testing the conveniently optimized enzyme mismatch cleavage method to clinical DNA diagnosis","volume":"107","author":"Niida","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/cge.12463","article-title":"CHIPS for genetic testing to improve a regional clinical genetic service","volume":"88","author":"Niida","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/elps.200700729","article-title":"Development of a simple and highly sensitive mutation screening system by enzyme mismatch cleavage with optimized conditions for standard laboratories","volume":"29","author":"Tsuji","year":"2008","journal-title":"Electrophoresis"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nbt.2514","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"Cibulskis","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1097\/GIM.0b013e31816b5cae","article-title":"ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007","volume":"10","author":"Richards","year":"2008","journal-title":"Genet. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:37:49Z","timestamp":1760143069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":52,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911175"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911175","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,22]]}}}