{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:23:49Z","timestamp":1791271429237,"version":"4.1.0"},"reference-count":25,"publisher":"BMJ","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1995,1]]},"abstract":"<jats:p>Neural tube defects (NTD) are among the most prevalent congenital malformations in man. Based on the molecular defect of Splotch, an established mouse model for NTD, and on the clinical association between NTD and Waardenburg syndrome (WS), mutations in the PAX3 gene can be expected to act as factors predisposing to human NTD. To test this hypothesis, 39 patients with familial NTD were screened by SSC analysis for mutations in exons 2 to 6 of the human PAX3 gene. One patient with lumbosacral meningomyelocele was identified with a 5 bp deletion in exon 5 approximately 55 bp upstream of the conserved homeodomain. The deletion causes a frameshift with a stop codon almost immediately after the mutated site. Clinical investigation of the index patient indicated mild signs of WS type I. Varying signs of this syndrome were found to cosegregate with the mutation in the family. Our results support the hypothesis that mutations in the gene for PAX3 can predispose to NTD, but also show that, in general, mutations within or near the conserved domains of the PAX3 protein are only very infrequently involved in familial NTD.<\/jats:p>","DOI":"10.1136\/jmg.32.1.52","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:23:16Z","timestamp":1226330596000},"page":"52-56","source":"Crossref","is-referenced-by-count":53,"title":["A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome."],"prefix":"10.1136","volume":"32","author":[{"given":"F A","family":"Hol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B C","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M P","family":"Geurds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R A","family":"Mullaart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F G","family":"Barr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R A","family":"Macina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E C","family":"Mariman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[1995,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0301-0082(90)90037-H","article-title":"The embryonic development of mammalian neural tube defects","volume":"35","author":"Copp, A.J.; Brook, F.A.; Estibeiro, P.; Shum, A.S.W.; Cockroft, D.L.","year":"1990","unstructured":"Copp AJ, Brook FA, Estibeiro P, Shum ASW, Cockroft DL. The embryonic development of mammalian neural tube defects. Prog Neurobiol 1990;35:363-403.","journal-title":"Prog Neurobiol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/ajmg.1320440426","article-title":"Parental sex effect in spina bifida: a role for genomic imprinting?","volume":"44","author":"Chatkupt, S.; Lucek, P.R.; Koenigsberger, R.; Johnson, W.G.","year":"1992","unstructured":"Chatkupt S, Lucek PR, Koenigsberger R, Johnson WG. Parental sex effect in spina bifida: a role for genomic imprinting? Am J Med Genet 1992;44:508-12.","journal-title":"Am J Med Genet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1136\/jmg.29.10.695","article-title":"Sex ratios of affected and transmitting members of multiple case families with neural tube defects","volume":"29","author":"Mariman, E.C.M.; Hamel, B.C.J.","year":"1992","unstructured":"Mariman ECM, Hamel BCJ. Sex ratios of affected and transmitting members of multiple case families with neural tube defects. J Med Genet 1992;29:695-8.","journal-title":"J Med Genet"},{"key":"ref_4","first-page":"452","article-title":"Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family","volume":"93","author":"true","year":"1994","unstructured":"Hol FA, Geurds MPA, Jensson 0, et al. Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family. Hum Genet 1994;93:452-6.","journal-title":"Hum Genet"},{"key":"ref_5","article-title":"Genetic variants and strains of the laboratory mouse","author":"Lyon, M.F.; Searle, A.G.","year":"1990","unstructured":"Lyon MF, Searle AG. Genetic variants and strains of the laboratory mouse. 2nd ed. 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S Afr MedJ7 1984;66:256-61.","journal-title":"S Afr MedJ7"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1002\/ajmg.1320310424","article-title":"Cerebellar infarction in a patient with Waardenburg syndrome","volume":"31","author":"Narod, S.A.; Siegel-Bartelt, J.; Hoffman, H.J.","year":"1988","unstructured":"Narod SA, Siegel-Bartelt J, Hoffman HJ. Cerebellar infarction in a patient with Waardenburg syndrome. Am Jf Med Genet 1988;31:903-7.","journal-title":"Am Jf Med Genet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/ajmg.1320400113","article-title":"Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review","volume":"40","author":"Da-Silva, E.O.","year":"1991","unstructured":"Da-Silva EO. Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review. 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EMBO.7 1989; 8:1183-90."}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.32.1.52","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:19:27Z","timestamp":1760721567000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.32.1.52"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,1]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[1995,1,1]]},"published-print":{"date-parts":[[1995,1]]}},"alternative-id":["10.1136\/jmg.32.1.52"],"URL":"https:\/\/doi.org\/10.1136\/jmg.32.1.52","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,1]]}}}