Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Summary Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands 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 observed among individuals with CM1 (combined p = 2.4 × 10−10), including 3 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 were found to have significantly increased head circumference (p = 2.6 × 10−9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.