Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

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.

On the association between Chiari malformation type 1, bone mineral density and bone related genes

“…The fact that the cranial bone constriction is suspected to be the most common biologic mechanism leading to C1M suggests that variants in genes related with bone metabolism may be contributing to the malformation through an incorrect development of the cranial bone. This hypothesis is reinforced by the findings of several recent works which have found association of C1M with rare variants in genes involved in collagen metabolism ( Urbizu et al, 2021 ), in Wnt pathway genes ( Merello et al, 2017 ), or in cranial bone sutures ( Provenzano et al, 2021 ).…”

“…Nevertheless, this could also be a spurious finding, as it is only one individual. In order to elucidate the relationship between the C1M and bone mass, it would be crucial to measure the LS and FN BMD of the C1M patients from previous publications ( Boyles et al, 2006 ; Markunas et al, 2013 ; Urbizu et al, 2013 ; Markunas et al, 2014 ; Rosenblum et al, 2019 ; Gonçalves et al, 2019 ; Merello et al, 2017 ; Urbizu et al, 2021 ; Provenzano et al, 2021 ; Sadler et al, 2021 ), thus increasing the size of the cohort of patients with C1M and BMD.…”

“…Interestingly, MYO7A has been already associated with C1M under the autosomal recessive inheritance pattern in the work of Sadler et al (2021) , who found two missense variants in MYO7A (p.R1229Q and p.R605W) in a C1M patient. Actually, in the search for the genetic bases of C1M, 207 different genes have been found to date associated in some way with the phenotype under different segregation hypotheses ( Boyles et al, 2006 ; Markunas et al, 2013 ; Urbizu et al, 2013 ; Markunas et al, 2014 ; Rosenblum et al, 2019 ; Gonçalves et al, 2019 ; Merello et al, 2017 ; Urbizu et al, 2021 ; Provenzano et al, 2021 ; Sadler et al, 2021 ). Of these 207 genes, 5 were included in the bone panel that we used in the present study.…”

“…Of these 207 genes, 5 were included in the bone panel that we used in the present study. These are MYO7A , BMP1 , COL1A2 , DKK1 and LRP4 ( Merello et al, 2017 ; Urbizu et al, 2021 ; Sadler et al, 2021 ). Interestingly, in addition to MYO7A , we also have found a variant in BMP1 in one C1M patient (p.R371H in CH10, Supplementary Table 2).…”

Chiari I malformation management in patients with heritable connective tissue disorders

“… 5 The presence of varying cranial morphologies for CMI with comorbid CTDs has been suggested to represent distinct clinical subtypes of CMI. 12 …”