Abstract
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.