TY - JOUR
T1 - Rare and de novo coding variants in chromodomain genes in Chiari I malformation
AU - Sadler, Brooke
AU - Wilborn, Jackson
AU - Antunes, Lilian
AU - Kuensting, Timothy
AU - Hale, Andrew T.
AU - Gannon, Stephen R.
AU - McCall, Kevin
AU - Cruchaga, Carlos
AU - Harms, Matthew
AU - Voisin, Norine
AU - Reymond, Alexandre
AU - Cappuccio, Gerarda
AU - Burnetti-Pierri, Nicola
AU - Tartaglia, Marco
AU - Niceta, Marcello
AU - Leoni, Chiara
AU - Zampino, Giuseppe
AU - Ashley-Koch, Allison
AU - Urbizu, Aintzane
AU - Garrett, Melanie E.
AU - Soldano, Karen
AU - Macaya, Alfons
AU - Conrad, Donald
AU - Strahle, Jennifer
AU - Dobbs, Matthew B.
AU - Turner, Tychele N.
AU - Shannon, Chevis N.
AU - Brockmeyer, Douglas
AU - Limbrick, David D.
AU - Gurnett, Christina A.
AU - Haller, Gabe
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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.
AB - 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.
KW - Chiari I malformation
KW - chromodomain genes
KW - de novo mutations
KW - gene burden
KW - macrocephaly
KW - rare variants
KW - zebrafish disease model
UR - http://www.scopus.com/inward/record.url?scp=85099005679&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.12.001
DO - 10.1016/j.ajhg.2020.12.001
M3 - Article
C2 - 33352116
AN - SCOPUS:85099005679
SN - 0002-9297
VL - 108
SP - 100
EP - 114
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -