{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:36:48Z","timestamp":1791344208220,"version":"4.3.1"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T00:00:00Z","timestamp":1415836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Nemours Foundation Cluster","award":["P20GM103464"],"award-info":[{"award-number":["P20GM103464"]}]},{"name":"Nemours Foundation Cluster","award":["P20GM103446"],"award-info":[{"award-number":["P20GM103446"]}]},{"name":"Nemours Foundation Cluster","award":["1U54HG006542"],"award-info":[{"award-number":["1U54HG006542"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec><jats:label\/><jats:p>Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele\u2010related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low\u2010set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high\u2010pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu\u2013Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating <jats:italic>NOTCH3<\/jats:italic> mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo <jats:italic>NOTCH3<\/jats:italic> mutations were identified in six unrelated patients. One had a 26\u2009bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A\u2009&gt;\u2009T (pK2083*), c.6663C\u2009&gt;\u2009G (p.Y2221*) or c.6732C\u2009&gt;\u2009A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline\u2010glutamate\u2010serine\u2010threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated <jats:italic>NOTCH3<\/jats:italic> may cause gain\u2010of\u2010function through decreased clearance of the active intracellular product, resembling <jats:italic>NOTCH2<\/jats:italic> mutations in the clinically related Hajdu\u2013Cheney syndrome and contrasting the <jats:italic>NOTCH3<\/jats:italic> missense mutations causing CADASIL. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36863","type":"journal-article","created":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T16:29:15Z","timestamp":1415896155000},"page":"271-281","source":"Crossref","is-referenced-by-count":71,"title":["Truncating mutations in the last exon of <i>NOTCH3<\/i> cause lateral meningocele syndrome"],"prefix":"10.1002","volume":"167","author":[{"given":"Karen W.","family":"Gripp","sequence":"first","affiliation":[{"name":"Division of Medical Genetics A.I. duPont Hospital for Children Wilmington, Delaware, and Sidney Kimmel Medical School at T. Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.","family":"Robbins","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research A.I. duPont Hospital for Children Wilmington Delaware"},{"name":"Department of Biological Sciences University of Delaware Newark Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nara L.","family":"Sobreira","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Institute of Genetic Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Dane","family":"Witmer","sequence":"additional","affiliation":[{"name":"Center for Inherited Disease Research Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne M.","family":"Bird","sequence":"additional","affiliation":[{"name":"University of California San Diego and Rady Children's Hospital San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristiina","family":"Avela","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Helsinki University Central Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Makitie","sequence":"additional","affiliation":[{"name":"Children's Hospital Helsinki University Central Hospital and University of Helsinki, and Folkh\u00e4lsan Institute of Genetics Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Alves","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit Department of Medical Genetics Centro Hospitalar de S\u00e3o Jo\u00e3o Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Hogue","sequence":"additional","affiliation":[{"name":"Madigan Army Medical Center Tacoma Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine H.","family":"Zackai","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and Molecular Biology Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly F.","family":"Doheny","sequence":"additional","affiliation":[{"name":"Center for Inherited Disease Research Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Stabley","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research A.I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Sol\u2010Church","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research A.I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,11,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11632"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34085"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33510"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.230"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36301"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30526"},{"key":"e_1_2_8_8_1","article-title":"Lehman syndrome: A new syndrome for Pierre Robin Sequence","volume":"51","author":"Correia\u2010Sa I","year":"2013","journal-title":"Cleft palate\u2010Craniofacial Journal"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34075"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19970613)70:3<229::AID-AJMG4>3.0.CO;2-R"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22283"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.018"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/383707a0"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.778"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201649"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(77)80763-4"},{"key":"e_1_2_8_18_1","unstructured":"Li H. 2013. 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