Primary Reference: Sadler et al. AJHG. Dec. 21, 2020.
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. CHD8variations 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.
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