Am J Hum Genet.: co-auth.: group Reymond

Am J Hum Genet. 2020 Dec 14;S0002-9297(20)30437-7. doi: 10.1016/j.ajhg.2020.12.001. Online ahead of print.

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

Brooke Sadler 1Jackson Wilborn 2Lilian Antunes 3Timothy Kuensting 2Andrew T Hale 4Stephen R Gannon 5Kevin McCall 3Carlos Cruchaga 6Matthew Harms 7Norine Voisin 8Alexandre Reymond 8Gerarda Cappuccio 9Nicola Burnetti-Pierri 9Marco Tartaglia 10Marcello Niceta 10Chiara Leoni 11Giuseppe Zampino 11Allison Ashley-Koch 12Aintzane Urbizu 12Melanie E Garrett 12Karen Soldano 12Alfons Macaya 13Donald Conrad 14Jennifer Strahle 2Matthew B Dobbs 15Tychele N Turner 16Chevis N Shannon 4Douglas Brockmeyer 17David D Limbrick 2Christina A Gurnett 18Gabe Haller 19


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.

Keywords: Chiari I malformation; chromodomain genes; de novo mutations; gene burden; macrocephaly; rare variants; zebrafish disease model.

PMID: 33352116