{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:46:24Z","timestamp":1789670784493,"version":"4.0.1"},"reference-count":29,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique high-risk pedigree population resource and approach to identify rare candidate variants that likely predispose individuals to CM and protein structure prediction tools to identify pathogenicity mechanisms.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p>By using the Utah Population Database, the authors identified pedigrees with significantly increased numbers of members with CM diagnosis. From a separate DNA biorepository of 451 samples from CM patients and families, 32 CM patients belonging to 1 or more of 24 high-risk Chiari pedigrees were identified. Two high-risk pedigrees had 3 CM-affected relatives, and 22 pedigrees had 2 CM-affected relatives. To identify rare candidate predisposition gene variants, whole-exome sequence data from these 32 CM patients belonging to 24 CM-affected related pairs from high-risk pedigrees were analyzed. The I-TASSER package for protein structure prediction was used to predict the structures of both the wild-type and mutant proteins found here.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Sequence analysis of the 24 affected relative pairs identified 38 rare candidate Chiari predisposition gene variants that were shared by at least 1 CM-affected pair from a high-risk pedigree. The authors found a candidate variant in <jats:italic>HOXC4<\/jats:italic> that was shared by 2 CM-affected patients in 2 independent pedigrees. All 4 of these CM cases, 2 in each pedigree, exhibited a specific craniocervical bony phenotype defined by a clivoaxial angle less than 125\u00b0. The protein structure prediction results suggested that the mutation considered here may reduce the binding affinity of HOXC4 to DNA.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>Analysis of unique and powerful Utah genetic resources allowed identification of 38 strong candidate CM predisposition gene variants. These variants should be pursued in independent populations. One of the candidates, a rare <jats:italic>HOXC4<\/jats:italic> variant, was identified in 2 high-risk CM pedigrees, with this variant possibly predisposing patients to a Chiari phenotype with craniocervical kyphosis.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2022.10.jns22956","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T12:05:56Z","timestamp":1669377956000},"page":"266-274","source":"Crossref","is-referenced-by-count":6,"title":["A likely HOXC4 predisposition variant for Chiari malformations"],"prefix":"10.3171","volume":"139","author":[{"given":"Douglas L.","family":"Brockmeyer","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurosurgery, Department of Neurosurgery, University of Utah, Salt Lake City, Utah;"},{"name":"Intermountain Healthcare, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel H.","family":"Cheshier","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurosurgery, Department of Neurosurgery, University of Utah, Salt Lake City, Utah;"},{"name":"Intermountain Healthcare, Salt Lake City, Utah;"},{"name":"Huntsman Cancer Institute, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Stevens","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio C.","family":"Facelli","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Informatics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry","family":"Rowe","sequence":"additional","affiliation":[{"name":"Intermountain Healthcare, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Heiss","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Musolf","sequence":"additional","affiliation":[{"name":"Statistical Genetics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Viskochil","sequence":"additional","affiliation":[{"name":"Intermountain Healthcare, Salt Lake City, Utah;"},{"name":"Pediatrics, University of Utah, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina L.","family":"Allen-Brady","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Cannon-Albright","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, Salt Lake City, Utah;"},{"name":"Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"10","key":"b1","series-title":"Eur J Hum Genet","first-page":"1599","article-title":"Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing","volume":"27","author":"Musolf AM","year":"2019","unstructured":"Musolf AM, Ho WSC, Long KA,  Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing. 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