Dataset Information

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

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.

SUBMITTER: Sadler B

PROVIDER: S-EPMC7820723 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Sadler Brooke B Wilborn Jackson J Antunes Lilian L Kuensting Timothy T Hale Andrew T AT Gannon Stephen R SR McCall Kevin K Cruchaga Carlos C Harms Matthew M Voisin Norine N Reymond Alexandre A Cappuccio Gerarda G Brunetti-Pierri Nicola N Tartaglia Marco M Niceta Marcello M Leoni Chiara C Zampino Giuseppe G Ashley-Koch Allison A Urbizu Aintzane A Garrett Melanie E ME Soldano Karen K Macaya Alfons A Conrad Donald D Strahle Jennifer J Dobbs Matthew B MB Turner Tychele N TN Shannon Chevis N CN Brockmeyer Douglas D Limbrick David D DD Gurnett Christina A CA Haller Gabe G

American journal of human genetics 20201221 1

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 a ...[more]

PMID: 33352116

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Project description:Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.

Dataset Information

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

Publications

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

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