{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T17:15:11Z","timestamp":1788023711676,"version":"build-2784847793"},"reference-count":22,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>Occurring once in every 2000 live births, craniosynostosis (CS) is the most frequent cranial birth defect. Although the genetic etiologies of syndromic CS cases are well defined, the genetic cause of most nonsyndromic cases remains unknown.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p>The authors analyzed exome or RNA sequencing data from 876 children with nonsyndromic CS, including 291 case-parent trios and 585 additional probands. The authors also utilized the GeneMatcher platform and the Gabriella Miller Kids First genome sequencing project to identify additional CS patients with <jats:italic>AXIN1<\/jats:italic> mutations.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>The authors describe 11 patients with nonsyndromic CS harboring rare, damaging mutations in <jats:italic>AXIN1<\/jats:italic>, an inhibitor of Wnt signaling. AXIN1 regulates signaling upstream of key mediators of osteoblast differentiation. Three of the 6 mutations identified in trios occurred de novo in the proband, while 3 were transmitted from unaffected parents. Patients with nonsyndromic CS were highly enriched for mutations in <jats:italic>AXIN1<\/jats:italic> compared to both expectation (p = 0.0008) and exome sequencing data from &gt; 76,000 healthy controls (p = 2.3 \u00d7 10<jats:sup>\u22126<\/jats:sup>), surpassing the thresholds for genome-wide significance.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>These findings describe the first phenotype associated with mutations in <jats:italic>AXIN1<\/jats:italic>, with mutations identified in approximately 1% of nonsyndromic CS cases. The results strengthen the existing link between Wnt signaling and maintenance of cranial suture patency and have implications for genetic testing in families with CS.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2024.5.peds24115","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T02:20:44Z","timestamp":1719022844000},"page":"246-251","source":"Crossref","is-referenced-by-count":3,"title":["AXIN1 mutations in nonsyndromic craniosynostosis"],"prefix":"10.3171","volume":"34","author":[{"given":"Andrew T.","family":"Timberlake","sequence":"first","affiliation":[{"name":"Hansj\u00f6rg Wyss Department of Plastic Surgery, NYU Langone Medical Center, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kshipra","family":"Hemal","sequence":"additional","affiliation":[{"name":"Hansj\u00f6rg Wyss Department of Plastic Surgery, NYU Langone Medical Center, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas A.","family":"Gustafson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Developmental Biology and Regenerative Medicine, Seattle Children\u2019s Research Institute, University of Washington, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le Thi","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics, Rare Disease Unit, Medical Genetics Group, Vall Hebron Research Institute, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Slavotinek","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California;"},{"name":"Department of Pediatrics, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Developmental Biology and Regenerative Medicine, Seattle Children\u2019s Research Institute, University of Washington, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Persing","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"6","key":"b1","series-title":"Plast Reconstr Surg","first-page":"1508","article-title":"Genetics of nonsyndromic craniosynostosis","volume":"141","author":"Timberlake AT","year":"2018","unstructured":"Timberlake AT, Persing JA. Genetics of nonsyndromic craniosynostosis. Plast Reconstr Surg. 2018;141(6):1508\u20131516."},{"issue":"35","key":"b2","series-title":"Proc Natl Acad Sci U S A","first-page":"E7341","article-title":"De novo mutations in inhibitors of Wnt, BMP, and Ras\/ERK signaling pathways in non-syndromic midline craniosynostosis","volume":"114","author":"Timberlake AT","year":"2017","unstructured":"Timberlake AT, Furey CG, Choi J,  De novo mutations in inhibitors of Wnt, BMP, and Ras\/ERK signaling pathways in non-syndromic midline craniosynostosis. Proc Natl Acad Sci U S A. 2017;114(35):E7341\u2013E7347."},{"key":"b3","series-title":"eLife","first-page":"e20125","article-title":"Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles","volume":"5","author":"Timberlake AT","year":"2016","unstructured":"Timberlake AT, Choi J, Zaidi S,  Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles. eLife. 2016;5:e20125."},{"issue":"30","key":"b4","series-title":"Proc Natl Acad Sci U S A","first-page":"15116","article-title":"Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis","volume":"116","author":"Timberlake AT","year":"2019","unstructured":"Timberlake AT, Jin SC, Nelson-Williams C,  Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis. Proc Natl Acad Sci U S A. 2019;116(30):15116\u201315121."},{"issue":"9","key":"b5","series-title":"Nat Genet","first-page":"944","article-title":"A framework for the interpretation of de novo mutation in human disease","volume":"46","author":"Samocha KE","year":"2014","unstructured":"Samocha KE, Robinson EB, Sanders SJ,  A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46(9):944\u2013950."},{"issue":"2","key":"b6","series-title":"Am J Med Genet A","first-page":"290","article-title":"Single suture craniosynostosis: identification of rare variants in genes associated with syndromic forms","volume":"176","author":"Clarke CM","year":"2018","unstructured":"Clarke CM, Fok VT, Gustafson JA,  Single suture craniosynostosis: identification of rare variants in genes associated with syndromic forms. Am J Med Genet A. 2018;176(2):290\u2013300."},{"issue":"7793","key":"b7","series-title":"Nature","first-page":"122","article-title":"The evolutionary history of 2,658 cancers","volume":"578","author":"Gerstung M","year":"2020","unstructured":"Gerstung M, Jolly C, Leshchiner I,  The evolutionary history of 2,658 cancers. Nature. 2020;578(7793):122\u2013128."},{"issue":"1","key":"b8","series-title":"Cancer Lett","first-page":"1","article-title":"AXIN1 and AXIN2 variants in gastrointestinal cancers","volume":"355","author":"Mazzoni SM","year":"2014","unstructured":"Mazzoni SM, Fearon ER. AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett. 2014;355(1):1\u20138."},{"issue":"10","key":"b9","series-title":"Hum Mutat","first-page":"928","article-title":"GeneMatcher: a matching tool for connecting investigators with an interest in the same gene","volume":"36","author":"Sobreira N","year":"2015","unstructured":"Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928\u2013930."},{"issue":"7809","key":"b10","series-title":"Nature","first-page":"434","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski KJ","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G,  The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434\u2013443."},{"issue":"6","key":"b11","series-title":"Nat Genet","first-page":"694","article-title":"Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma","volume":"44","author":"Guichard C","year":"2012","unstructured":"Guichard C, Amaddeo G, Imbeaud S,  Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694\u2013698."},{"issue":"2","key":"b12","series-title":"Nat Med","first-page":"179","article-title":"WNT signaling in bone homeostasis and disease: from human mutations to treatments","volume":"19","author":"Baron R","year":"2013","unstructured":"Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179\u2013192."},{"issue":"2","key":"b13","series-title":"Dev Biol","first-page":"922","article-title":"Differential activation of canonical Wnt signaling determines cranial sutures fate: a novel mechanism for sagittal suture craniosynostosis","volume":"344","author":"Behr B","year":"2010","unstructured":"Behr B, Longaker MT, Quarto N. Differential activation of canonical Wnt signaling determines cranial sutures fate: a novel mechanism for sagittal suture craniosynostosis. Dev Biol. 2010;344(2):922\u2013940."},{"issue":"8","key":"b14","series-title":"PLoS One","first-page":"e70240","article-title":"Absence of endochondral ossification and craniosynostosis in posterior frontal cranial sutures of Axin2\u2212\/\u2212 mice","volume":"8","author":"Behr B","year":"2013","unstructured":"Behr B, Longaker MT, Quarto N. Absence of endochondral ossification and craniosynostosis in posterior frontal cranial sutures of Axin2\u2212\/\u2212 mice. PLoS One. 2013;8(8):e70240."},{"issue":"2","key":"b15","series-title":"Genesis","first-page":"98","article-title":"Generation of Axin1 conditional mutant mice","volume":"49","author":"Xie R","year":"2011","unstructured":"Xie R, Jiang R, Chen D. Generation of Axin1 conditional mutant mice. Genesis. 2011;49(2):98\u2013102."},{"key":"b16","series-title":"Bone Res","first-page":"31","article-title":"Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation","volume":"8","author":"Shu B","year":"2020","unstructured":"Shu B, Zhao Y, Zhao S,  Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation. Bone Res. 2020;8:31."},{"issue":"8","key":"b17","series-title":"Development","first-page":"1995","article-title":"The role of Axin2 in calvarial morphogenesis and craniosynostosis","volume":"132","author":"Yu HM","year":"2005","unstructured":"Yu HM, Jerchow B, Sheu TJ,  The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development. 2005;132(8):1995\u20132005."},{"issue":"20","key":"b18","series-title":"N Engl J Med","first-page":"1513","article-title":"High bone density due to a mutation in LDL-receptor-related protein 5","volume":"346","author":"Boyden LM","year":"2002","unstructured":"Boyden LM, Mao J, Belsky J,  High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513\u20131521."},{"issue":"1","key":"b19","series-title":"Hum Genet","first-page":"21","article-title":"De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis","volume":"142","author":"Timberlake AT","year":"2023","unstructured":"Timberlake AT, Kiziltug E, Jin SC,  De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Hum Genet. 2023;142(1):21\u201332."},{"issue":"7","key":"b20","series-title":"J Bone Miner Res","first-page":"1254","article-title":"An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation","volume":"20","author":"Kwee ML","year":"2005","unstructured":"Kwee ML, Balemans W, Cleiren E,  An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation. J Bone Miner Res. 2005;20(7):1254\u20131260."},{"key":"b21","series-title":"Hum Genome Var","first-page":"14","article-title":"Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis","volume":"5","author":"Timberlake AT","year":"2018","unstructured":"Timberlake AT, Wu R, Nelson-Williams C,  Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis. Hum Genome Var. 2018;5:14."},{"issue":"5","key":"b22","series-title":"Am J Hum Genet","first-page":"846","article-title":"De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis","volume":"110","author":"Timberlake AT","year":"2023","unstructured":"Timberlake AT, McGee S, Allington G,  De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis. Am J Hum Genet. 2023;110(5):846\u2013862."}],"container-title":["Journal of Neurosurgery: Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg-pediatr\/34\/3\/article-p246.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg-pediatr\/34\/3\/article-p246.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg-pediatr\/34\/3\/article-p246.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T13:07:15Z","timestamp":1733490435000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg-pediatr\/34\/3\/article-p246.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,1]]},"references-count":22,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.3171\/2024.5.peds24115","relation":{},"ISSN":["1933-0707","1933-0715"],"issn-type":[{"value":"1933-0707","type":"print"},{"value":"1933-0715","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,1]]}}}