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

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

Abstract

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