{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:17:48Z","timestamp":1760833068255,"version":"build-2065373602"},"reference-count":24,"publisher":"BMJ","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1996,1]]},"abstract":"<jats:p>Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease with a high mutation rate. It is clinically a very variable disorder and hamartomas can occur in many different organs. TSC shows genetic heterogeneity; one gene, TSC1, is on chromosome 9q34, and the second gene, TSC2, on chromosome 16p13.3. Clinical criteria for diagnosis have been established, but diagnosis of patients with minimal expression of the disease can be very difficult. In children the phenotype is often incomplete or not fully assessable. Hence mildly affected subjects, at risk for severely affected offspring, may remain undiagnosed. The detection of (small) mutations in the tuberous sclerosis gene located on chromosome 16 (TSC2) has recently become possible and may be helpful in the diagnosis of ambiguous cases. To our knowledge, this is the first report of a point mutation in the TSC2 gene in a familial case of tuberous sclerosis. A nonsense mutation was detected in a family in which the father had only minor signs hinting at tuberous sclerosis. The son had multiple cardiac tumours and white patches, but full clinical investigation was impossible in this child. This case illustrates that mutation analysis can contribute to a diagnosis of tuberous sclerosis in families with an incomplete phenotype.<\/jats:p>","DOI":"10.1136\/jmg.33.1.47","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:37:21Z","timestamp":1226331441000},"page":"47-51","source":"Crossref","is-referenced-by-count":20,"title":["Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex."],"prefix":"10.1136","volume":"33","author":[{"given":"R","family":"Vrtel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Verhoef","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Bouman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M M","family":"Maheshwar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Nellist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A J","family":"van Essen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P L","family":"Bakker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C J","family":"Hermans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M T","family":"Bink-Boelkens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R M","family":"van Elburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Hoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Lindhout","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D J","family":"Halley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A M","family":"van den Ouweland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1996,1,1]]},"reference":[{"key":"ref_1","article-title":"Tuberous sclerosis","author":"Gomez, M.R.","year":"1988","unstructured":"Gomez MR. 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Evidence for genetic heterogeneity in tuberous sclerosis. _7 Med Genet 1989;26: 511-16.","journal-title":"_7 Med Genet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1749-6632.1991.tb37767.x","article-title":"Genetic heterogeneity in tuberous sclerosis: study of a large collaborative data set","volume":"615","author":"Haines, J.L.; Amos, J.; Attwood, J.","year":"1991","unstructured":"Haines JL, Amos J, Attwood J, et al. Genetic heterogeneity in tuberous sclerosis: study of a large collaborative data set. Ann NYAcad Sci 1991;615:256-64.","journal-title":"Ann NYAcad Sci"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1749-6632.1991.tb37771.x","article-title":"An attempt to map two genes for tuberous sclerosis using novel two-point methods","volume":"615","author":"Povey, S.; Attwood, J.; Janssen, L.A.J.","year":"1991","unstructured":"Povey S, Attwood J, Janssen LAJ, et al. 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Cell 1990;62: 193-201.","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/humu.1380040202","article-title":"Molecular basis of neurofibromatosis type 1 (NFl): mutation analysis and polymorphisms in the NF1 gene","volume":"4","author":"Upadhyaya, M.; Shaw, D.J.; Harper, P.S.","year":"1994","unstructured":"Upadhyaya M, Shaw DJ, Harper PS. Molecular basis of neurofibromatosis type 1 (NFl): mutation analysis and polymorphisms in the NF1 gene. Hum Mutat 1994;4: 83-101.","journal-title":"Hum Mutat"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1136\/adc.72.6.471","article-title":"Tuberous sclerosis","volume":"70","author":"Webb, D.W.; Osborne, J.P.","year":"1995","unstructured":"Webb DW, Osborne JP. Tuberous sclerosis. Arch Dis Child 1995;70:471-4.","journal-title":"Arch Dis Child"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0030-4220(75)90158-9","article-title":"'s Gravenmade EJ. Enamel defects associated with tuberous sclerosis","volume":"40","author":"Hoff, M.; van Grunsven, M.F.; Jongbloed, W.L.","year":"1975","unstructured":"Hoff M, van Grunsven MF, Jongbloed WL, 's Gravenmade EJ. Enamel defects associated with tuberous sclerosis. Oral Surg 1975;40:261-9.","journal-title":"Oral Surg"},{"key":"ref_19","first-page":"615","article-title":"Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria","author":"Gomez, M.R.","year":"1991","unstructured":"Gomez MR. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. 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Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphism. Proc Natl Acad Sci USA 1989;86:2766-70.","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_22","volume-title":"Current protocols in human genetics","author":"Dracopoli, N.C.; Haines, J.L.; Korf, B.R.","year":"1994","unstructured":"Dracopoli NC, Haines JL, Korf BR, et al (eds). Current protocols in human genetics. New York: John Wiley, 1994."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/BF00201608","article-title":"Refined localization of TSC 1 by combined analysis of 9q34 and 16p 13 data in 14 tuberous sclerosis families","volume":"94","author":"Janssen, B.; Sampson, J.; van der Est, M.","year":"1994","unstructured":"Janssen B, Sampson J, van der Est M, et al. Refined localization of TSC 1 by combined analysis of 9q34 and 16p 13 data in 14 tuberous sclerosis families. Hum Genet 1994; 94:437-40.","journal-title":"Hum Genet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8125","DOI":"10.1093\/nar\/15.20.8125","article-title":"An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs","volume":"20","author":"Kozak, M.","year":"1987","unstructured":"Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. 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