{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:25:02Z","timestamp":1790105102545,"version":"4.0.1"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Pontocerebellar hypoplasia type 8(PCH8) is a rare neurodegenerative disorder, reportedly caused by pathogenic variants of the <jats:italic>CHMP1A<\/jats:italic> in autosomal recessive inheritance, and <jats:italic>CHMP1A<\/jats:italic> variants have also been implicated in other diseases, and yet none of the prenatal fetal features were reported in PCH8. In this study, we investigated the phenotype and genotype in a human subject with global developmental delay, including clinical data from the prenatal stage through early childhood. Prenatally, the mother had polyhydramnios, and the bilateral ventricles of the fetus were slightly widened. Postnatally, the infant was observed to have severely delayed psychomotor development and was incapable of visual tracking before 2\u2009years old and could not fix on small objects. The young child had hypotonia, increased knee tendon reflex, as well as skeletal malformations, and dental crowding; she also had severe and recurrent pulmonary infections. Magnetic resonance imaging of the brain revealed a severe reduction of the cerebellum (vermis and hemispheres) and a thin corpus callosum. Through whole exome sequencing and whole genomics sequencing, we identified two novel compound heterozygous variations in <jats:italic>CHMP1A<\/jats:italic> [c.53\u2009T\u2009&amp;gt;\u2009C(p.Leu18Pro)(NM_002768.5) and exon 1 deletion region (NC_000016.10:g.89656392_89674382del)]. cDNA analysis showed that the exon1 deletion region led to the impaired expression, and functional verification with zebrafish embryos using base edition indicated variant c.53\u2009T\u2009&amp;gt;\u2009C (p.Leu18Pro), causing dysplasia of the cerebellum and pons. These results provide further evidence that <jats:italic>CHMP1A<\/jats:italic> variants in a recessive inheritance pattern contribute to the clinical characteristics of PCH8 and further expand our knowledge of the phenotype and genotype spectrum of PCH8.<\/jats:p>","DOI":"10.3389\/fneur.2023.1228218","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T07:50:18Z","timestamp":1695109818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence"],"prefix":"10.3389","volume":"14","author":[{"given":"Tiantian","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bocheng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotang","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1002\/ajmg.c.31403","article-title":"Pontocerebellar hypoplasia","author":"Rudnik-Sch\u00f6neborn","year":"2014","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1038\/ng.2425","article-title":"CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development","volume":"44","author":"Mochida","year":"2012","journal-title":"Nat Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1111\/cge.13463","article-title":"Effect of inbreeding on intellectual disability revisited by trio sequencing","volume":"95","author":"Kahrizi","year":"2019","journal-title":"Clin Genet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum disorder","volume":"515","author":"Iossifov","year":"2014","journal-title":"Nature"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/nn.4598","article-title":"Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder","volume":"20","author":"Lim","year":"2017","journal-title":"Nat Neurosci"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1016\/j.ajhg.2019.11.003","article-title":"Sex-based analysis of de novo variants in neurodevelopmental disorders","volume":"105","author":"Turner","year":"2019","journal-title":"Am J Hum Genet"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13024-021-00455-2","article-title":"Identification of sixteen novel candidate genes for late onset Parkinson's disease","volume":"16","author":"Gialluisi","year":"2021","journal-title":"Mol Neurodegener"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/s41419-018-0311-9","article-title":"CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis","volume":"9","author":"Sun","year":"2018","journal-title":"Cell Death Dis"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.1038\/s41467-022-31034-8","article-title":"SpG and SpRY variants expand the CRISPR toolbox for genome editing in zebrafish","volume":"13","author":"Liang","year":"2022","journal-title":"Nat Commun"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e67882","DOI":"10.1371\/journal.pone.0067882","article-title":"A novel testis-enriched gene Spata33 is expressed during spermatogenesis","volume":"8","author":"Chen","year":"2013","journal-title":"PLoS One"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1242\/jcs.114.13.2395","article-title":"CHMP1 functions as a member of a newly defined family of vesicle trafficking proteins","volume":"114","author":"Howard","year":"2001","journal-title":"J Cell Sci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.1242\/jcs.114.13.2383","article-title":"CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression","volume":"114","author":"Stauffer","year":"2001","journal-title":"J Cell Sci"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1228218\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T07:50:21Z","timestamp":1695109821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1228218\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,18]]},"references-count":12,"alternative-id":["10.3389\/fneur.2023.1228218"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1228218","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,18]]},"article-number":"1228218"}}