--- title: Rare and De Novo Coding Variants in Chromodomain Genes in Chiari I description: Chiari I malformation CM1 is caused by rare and de novo variants in chromodomain genes. Scientists from Washington University in St. Louis performed whole-exome sequencing (WES). They found variants in CHD8 and CHD3. Individuals with CM1 had macrocephaly. image: https://variants.varsome.com/hubfs/GV_1200x628_LabApplication.jpg --- [![VarSome](https://variants.varsome.com/hubfs/VarSome_February2020%20Theme/Images/logo.png)](https://varsome.com/) - Editions - [More about VarSome.com](https://varsome.com/varsome-editions/varsome/) - [More about VarSome Premium](https://varsome.com/varsome-editions/varsome-premium/) - [More about VarSome Clinical](https://varsome.com/varsome-editions/varsome-clinical/) - [Learn more about APIs](https://varsome.com/information/varsome-api-info/) - About - Resources - [Library](https://varsome.com/library/) - [Documentation](https://docs.varsome.com/) - [Query types](https://varsome.com/about/examples/) - [IVDR](https://landing.varsome.com/ivdr-whitepaper) - [Germline Classification](https://varsome.com/about/resources/acmg-implementation/) - [Somatic Classification](https://varsome.com/about/resources/amp-implementation/) - Partners - [Distributors](https://varsome.com/distributors/) - [Partners](https://varsome.com/partners/) - [Become a partner](https://landing.varsome.com/become-varsome-partner) - General - [The Company](https://saphetor.com/about/) - [Cite VarSome](https://varsome.com/about/varsome-citations/) - [Link to VarSome](https://varsome.com/how-do-i-create-link-varsome/) - [Contact](https://landing.varsome.com/contact) - [Community](https://varsome.com/community-contributions/) - [Blog](https://blog.varsome.com/) [Variant Views](https://variants.varsome.com/en/tag/variant-views) # Rare and De Novo Coding Variants in Chromodomain Genes in Chiari I By [Malorye Branca](https://variants.varsome.com/en/author/malorye-branca) on March, 3 2021 ### Categories - Select a Topic - [All](https://variants.varsome.com/en) - [Variant Views](https://variants.varsome.com/en/tag/variant-views) - [Community](https://variants.varsome.com/en/tag/community) ### Stay up to date ##### Search The Blog [Back to main Blog](https://variants.varsome.com/en) [![](https://variants.varsome.com/hs-fs/hubfs/mabranca.jpg?height=100&name=mabranca.jpg)](https://variants.varsome.com/en/author/malorye-branca#blog-listing-section) ###### [Malorye Branca](https://variants.varsome.com/en/author/malorye-branca#blog-listing-section) Primary Reference: [Sadler et al. AJHG. Dec. 21, 2020.](https://doi.org/10.1016/j.ajhg.2020.12.001) Genes:  *[CHD8](https://varsome.com/gene/CHD8) and [CHD3](https://varsome.com/gene/CHD3).* Chiari I malformation (CM1) describes displacement of the cerebellum through the foramen magnum into the spinal canal, and it is one of the most common pediatric neurological conditions. Patients can present with neurological symptoms, including severe headaches and sensory or motor deficits. Sadler *et al.* conducted whole-exome sequencing (WES) on 668 CM1 patients and 232 family members and performed gene-burden and *de novo* enrichment analyses. A significant enrichment of rare and *de novo* non-synonymous variants in chromodomain (CHD) genes was seen among individuals with CM1 (combined p = 2.4 × 10 −10), including three *de novo* loss-of-function variants in *CHD8* (LOF enrichment p = 1.9 × 10 −10) and a significant burden of rare transmitted variants in *CHD3* (p = 1.8 × 10 −6). Overall, individuals with CM1 had significantly increased head circumference (p = 2.6 × 10 −9), and many with *CHD* rare variants had macrocephaly. Further, they found that haploinsufficiency for *CDH8* in zebrafish led to macrocephaly and posterior hindbrain displacement, similar to what is seen in CM1. They noted that: "These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis."   **Additional resource:**   *The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients*. [Ostrowski et al. Am J Med Genet C Semin Med Genet. 2019](https://pubmed.ncbi.nlm.nih.gov/31721432/). *CHD8*variations have been associated with an overgrowth syndrome that includes intellectual disability, as well as height and/or head circumference at least 2 standard deviations above the mean. This study reports on 27 unrelated patients with pathogenic or likely pathogenic *CHD8* variants.  All the patients presented with intellectual disability and most had a height and/or head circumference at least ≥2 standard deviations above the mean.   **Call to Readers:** Submit comments below, and suggest new topics to:  **press@varsome.com** [Previous Post](https://variants.varsome.com/en/premature-ovarian-failure) [Next Post](https://variants.varsome.com/en/genetic-mechanisms-of-critical-illness-in-covid-19) #### Submit a Comment ### Stay up to date ## Latest News [See all blog posts](https://blog.varsome.com) ![](https://variants.varsome.com/hubfs/VarSome_February2020%20Theme/Images/logo.png) - VarSome Suite - [VarSome.com](https://saphetor.com/varsome-editions/varsome/) - [VarSome Premium](https://saphetor.com/varsome-editions/varsome-premium/) - [VarSome Clinical](https://saphetor.com/varsome-editions/varsome-clinical/) - [VarSome API](https://varsome.com/information/varsome-api-info/) - System Status - [System Status](http://status.saphetor.com/) - Resources - [Query Examples](https://varsome.com/about/examples/) - [Documentation](https://docs.varsome.com/) - [Help Center](https://docs.varsome.com/en) - [Cite VarSome](https://news.varsome.com/en/cite-varsome-the-human-genomic-variant-search-engine) - The Company - [About Saphetor SA](https://saphetor.com/about/) - [News](https://blog.varsome.com) - [Distributors](https://landing.varsome.com/distributors) - [Contact](https://saphetor.com/contact/) - Legal - [Terms of Use](https://varsome.com/terms/) - [Privacy Policy](https://varsome.com/privacy/) VarSome Suite is brought to you by [Saphetor SA](https://saphetor.com). © 2024 Saphetor SA – All Rights Reserved.