Abstract
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.
Highlights
Chiari Malformations (CMs) are a group of malformations characterized by a downward herniation of the caudal part of the cerebellum and/or medulla oblongata into the spinal canal
Among the remaining 24 variants, seven were in pathways involved in angiogenesis (ADGRB3, ADGRA2) or the extracellular matrix (COL6A5, COL7A1, DST, COL15A1, ITIH5) (Table 1) and were confirmed by Sanger sequencing
Variants located in COL6A5, ADGRB3 and DST were present in the remaining affected sibling, but not in other family members who were not diagnosed with Chiari Malformation Type 1 (CM-1) (II.2, III.2 and III.3), suggesting cosegregation with the disease in the family (Fig 1A and 1B)
Summary
Chiari Malformations (CMs) are a group of malformations characterized by a downward herniation of the caudal part of the cerebellum and/or medulla oblongata into the spinal canal. Genetic and genomic technologies have shifted towards generation sequencing (NGS) approaches Application of these approaches to CM-1 could improve the identification of causal variants in family and cohort studies. Another study performed exome sequencing on seven large multiplex Russian CM-1 families and linkage analysis suggested two chromosomal regions on 1q43-44 and 12q23-24.11, but the actual gene(s) and variants responsible were not definitively identified [14]. These findings highlight the potential power of NGS in identifying CM-1 genes, and underscore the extensive genetic heterogeneity and the challenges for replicating genetic findings for this condition. Our findings implicate several extracellular matrix and bone development genes in risk for CM-1, and suggest that rare variants in collagen genes are commonly present in CM-1
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