AvŞar Timuçin, ÇaliŞ Şeyma, Yilmaz Baran, Demİrcİ OtluoĞlu Gülden, Holyavkİn Can, KiliÇ Türker
Department of Medical Biology, School of Medicine, Bahçeşehir University, İstanbul Turkey.
Neuroscience Program, Health Sciences Institute, Bahçeşehir University, İstanbul Turkey.
Turk J Biol. 2020 Dec 14;44(6):449-456. doi: 10.3906/biy-2009-19. eCollection 2020.
Chiari malformation type I (CMI) is a brain malformation that is characterized by herniation of the cerebellum into the spinal canal. Chiari malformation type I is highly heterogeneous; therefore, an accurate explanation of the pathogenesis of the disease is often not possible. Although some studies showed the role of genetics in CMI, the involvement of genetic variations in CMI pathogenesis has not been thoroughly elucidated. Therefore, in the current study we aim to reveal CMI-associated genomic variations in familial cases.Four CMI patients and 7 unaffected healthy members of two distinct families were analyzed. A microarray analysis of the affected and unaffected individuals from two Turkish families with CMI was conducted. Analyses of single nucleotide variations (SNVs) and copy number variations (CNVs) were performed by calculation of B allele frequency (BAF) and log R ratio (LRR) values from whole genome SNV data. Two missense variations, OLFML2A (rs7874348) and SLC4A9 (rs6860077), and a 5'UTR variation of COL4A1 (rs9521687) were significantly associated with CMI. Moreover, 12 SNVs in the intronic regions of FAM155A, NR3C1, TRPC7, ASTN2, and TRAF1 were determined to be associated with CMI. The CNV analysis showed that the 11p15.4 chromosome region is inherited in one of the families. The use of familial studies to explain the molecular pathogenesis of complex diseases such as CMI is crucial. It has been suggested that variations in OLFML2A, SLC4A9, and COL4A1 play a role in CMI molecular pathogenesis. The CNV analysis of individuals in both families revealed a potential chromosomal region, 11p15.4, and risk regions that are associated with CMI.
I型Chiari畸形（CMI）是一种脑部畸形，其特征是小脑疝入椎管。I型Chiari畸形具有高度异质性；因此，通常无法准确解释该疾病的发病机制。尽管一些研究显示了遗传学在CMI中的作用，但CMI发病机制中基因变异的参与尚未得到充分阐明。因此，在本研究中，我们旨在揭示家族性病例中与CMI相关的基因组变异。对来自两个不同家族的4例CMI患者和7名未受影响的健康成员进行了分析。对两个患有CMI的土耳其家族中受影响和未受影响的个体进行了微阵列分析。通过计算全基因组单核苷酸变异（SNV）数据中的B等位基因频率（BAF）和对数R比率（LRR）值，对单核苷酸变异（SNV）和拷贝数变异（CNV）进行分析。两个错义变异，OLFML2A（rs7874348）和SLC4A9（rs6860077），以及COL4A1的一个5'UTR变异（rs9521687）与CMI显著相关。此外，确定FAM155A、NR3C1、TRPC7、ASTN2和TRAF1内含子区域的12个SNV与CMI相关。CNV分析表明，11p15.4染色体区域在其中一个家族中是可遗传的。利用家族研究来解释CMI等复杂疾病的分子发病机制至关重要。有人提出，OLFML2A、SLC4A9和COL4A1的变异在CMI分子发病机制中起作用。对两个家族个体的CNV分析揭示了一个潜在的染色体区域11p15.4以及与CMI相关的风险区域。
