Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1.
Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1.
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DOI：
10.1371/journal.pone.0251289
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Ashley-Koch A
中科院分区：
文献类型：
--
作者：
Urbizu A;Garrett ME;Soldano K;Drechsel O;Loth D;Marcé-Grau A;Mestres I Soler O;Poca MA;Ossowski S;Macaya A;Loth F;Labuda R;Ashley-Koch A
1型Chiari畸形（CM-1）的特征是枕骨大孔下方小脑扁桃体突出，伴有头痛和其他神经系统症状。颅骨收缩被认为是导致CM-1最常见的生物学机制。然而，其他机制也可能起作用，特别是在结缔组织疾病（CTDs）的存在下，如Ehlers Danlos综合征（EDS）。越来越多的数据表明，伴有结缔组织疾病（CTD+）的CM-1可能与无CTD （CTD-）的CM-1具有不同的病理机制和不同的遗传危险因素。为了确定CM-1遗传风险变异，我们对来自西班牙的一个大的、多重的家族进行了全外显子组测序，并对186名患有CM-1的成年高加索女性进行了靶向测序。靶向测序捕获了21个CM-1和EDS候选基因的编码区，其中包括两个在西班牙家族中发现的基因。通过基因负担分析，我们比较了CM-1病例中检测到的罕见功能性变异的频率与gnomAD中公开的种族匹配对照的频率。第二次分析比较了CTD+和CTD- CM-1病例中这些基因的罕见变异的存在。在西班牙家族中，COL6A5、ADGRB3和DST与CM-1共分离的罕见变异。COL7A1的变异存在于受影响和未受影响的家庭成员中。在靶向测序分析中，6个基因（COL7A1、COL5A2、COL6A5、COL1A2、VEGFB、FLT1）的罕见变异在CM-1病例中明显高于公共对照。总的来说，47%的CM-1病例在四个重要的胶原蛋白基因中至少有一个出现罕见的变异，10%的病例在多个重要的胶原蛋白基因中存在变异。此外，26%的CM-1病例表现出COL6A5基因的罕见变异。我们还发现了两个基因（COL7A1, COL3A1），它们的罕见变异负担在CTD+和CTD- CM-1病例之间存在显著差异。与CTD+患者相比，CTD+患者COL7A1变异的比例更高，而CTD+患者COL3A1罕见变异的比例低于CTD-患者。总之，几种胶原蛋白基因的罕见变异在CM-1病例中特别常见，在西班牙多重家族中COL6A5基因与CM-1共分离。COL6A5先前与肌肉骨骼表型相关，但这是首次与CM-1相关。我们的研究结果强调了胶原基因中罕见的遗传变异对CM-1的贡献，并表明CM-1在出现和不出现CTD症状时是由不同的基因驱动的。
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.
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影响因子：
2.9
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