{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:32:19Z","timestamp":1787671939787,"version":"build-2736575974"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chiari 1 malformation (CM1) is the most common congenital malformation of the human hindbrain. Although prior studies have implicated chromatin-remodeling genes in CM1, the de novo genetic architecture and underlying neurodevelopmental mechanisms remain incompletely defined.<\/jats:p>\n                  <jats:p>To investigate the molecular genetics of a novel familial form of CM1 linked with syringomyelia and tethered cord and determine whether rare, damaging de novo variants (DNVs) contribute to sporadic CM1 risk with gene- and pathway-level resolution, we performed whole-exome sequencing in an ultra-rare multigenerational family with CM1 and associated spinal pathology, and in the largest assembled trio-based cohort to date, comprising 1,585 proband\u2013parent trios with sporadic, idiopathic CM1 (2017-2025). The comparison cohort included 1,798 unaffected control siblings. Clinical phenotyping was by systematic medical record review. Structural domain mapping, in silico modeling, and integration with single-cell transcriptomic data from developing human cerebellum was conducted to assess biological plausibility.<\/jats:p>\n                  <jats:p>A heterozygous loss-of-function variant in CHD3 segregated with CM1 and syringomyelia in a multigenerational family. In the trio-based cohort, rare protein-altering DNVs were significantly enriched across multiple chromodomain helicase DNA-binding (CHD) genes, including CHD1, CHD3, CHD4, and CHD8, exceeding gene-specific mutation expectations (protein-damaging variants: P = 1.3 \u00d7 10\u22129; predicted loss-of-function variants: P = 8.6 \u00d7 10\u22125). CHD1 contained two pathogenic DNVs (p.A999D and p.E984K). CHD4 (p.D744N, p.T1813P, and p.I1102T) and CHD8 (p.R1402X, p.R1472X, and p.R2035X) each contained three new DNVs. Variants clustered within conserved ATPase, helicase, and chromodomain regions essential for chromatin remodeling, and these patients frequently had comorbid developmental delay and related neurodevelopmental features. Single-cell transcriptomic analyses demonstrated enrichment in Purkinje cells and inhibitory neurons of midgestational cerebellum, where CHD gene products form a coherent chromatin-regulatory network.<\/jats:p>\n                  <jats:p>Rare, large-effect DNVs that disrupt chromatin-remodeling programs contribute to sporadic CM1, implicating genetically encoded dysregulation of cerebellar development as a central disease mechanism. Exome sequencing may complement surgical evaluation of children with sporadic CM1, particularly when accompanied by neurodevelopmental concerns, informing prognosis and family counseling.<\/jats:p>","DOI":"10.1093\/brain\/awag282","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T11:40:05Z","timestamp":1787398805000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>De novo<\/i>\n                    chromatin remodelling variants in sporadic Chiari 1 malformation"],"prefix":"10.1093","author":[{"given":"Neel H","family":"Mehta","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett","family":"Allington","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]},{"name":"Department of Neurology, Columbia University Vagelos College of Physicians & Surgeons and New York Presbyterian Hospital , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C","family":"Davalan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kedous Y","family":"Mekbib","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Mayo Clinic Hospital , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T","family":"Hale","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Alabama at Birmingham , Birmingham, AL 35294 ,","place":["USA"]},{"name":"Department of Human Biology and Neuroscience Institute, University of Cape Town , Cape Town, 7701 ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baojian","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P","family":"Shofi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth L","family":"Alper","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center , Boston, MA 02215 ,","place":["USA"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Johns Hopkins University , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-2925","authenticated-orcid":false,"given":"Shozeb","family":"Haider","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University College London , London, WC1E 6BT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"McGee","sequence":"additional","affiliation":[{"name":"GeneDx, Gaithersburg , Maryland, MD 20877 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-7547","authenticated-orcid":false,"given":"Kristopher T","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]},{"name":"Division of Genetics & Genomics, Boston Children's Hospital , Boston, MA 02215 ,","place":["USA"]},{"name":"Harvard PhD Program in Neuroscience (PiN), Harvard University , Cambridge, MA 02138 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,25]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag282\/70784302\/awag282.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag282\/70784302\/awag282.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:09:41Z","timestamp":1787670581000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag282\/8770351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag282","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"article-number":"awag282"}}