Genome-wide identification of Chiari malformation type I associated candidate genes and chromosomal variations

Abstract

Chiari malformation type I (CMI) is a brain malformation that is characterized by herniation of the cerebellum into the spinalcanal. Chiari malformation type I is highly heterogeneous; therefore, an accurate explanation of the pathogenesis of the disease is oftennot possible. Although some studies showed the role of genetics in CMI, the involvement of genetic variations in CMI pathogenesis hasnot 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 andunaffected individuals from two Turkish families with CMI was conducted. Analyses of single nucleotide variations (SNVs) and copynumber variations (CNVs) were performed by calculation of B allele frequency (BAF) and log R ratio (LRR) values from whole genomeSNV 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 TRAF1were determined to be associated with CMI. The CNV analysis showed that the 11p15.4 chromosome region is inherited in one of thefamilies. 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 individualsin both families revealed a potential chromosomal region, 11p15.4, and risk regions that are associated with CMI.