Timuçin AVŞAR, Şeyma ÇALIŞ, Türker KILIÇ, Baran YILMAZ, Gülden DEMİRCİ OTLUOĞLU, Can HOLYAVKİN

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

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.

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Abdul-Wajid S, Morales-Diaz H, Khairallah SM, Smith WC (2015). T-type calcium channel regulation of neural tube closure and EphrinA/EPHA expression. Cell Reports 13: 829-839.
Beck B, Zholos A, Sydorenko V, Roudbaraki M, Lehen’kyi V et al. (2006). TRPC7 is a receptor-operated DAG-activated channel in human keratinocytes. Journal of Investigative Dermatology 126: 1982-1993.
Behesti H, Fore TR, Wu P, Horn Z, Leppert M et al. (2018). ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proceedings of the National Academy of Sciences of the United States of America 115: E9717-E9726.
Boyles AL, Enterline DS, Hammock PH, Siegel DG, Slifer SH et al. (2006). Phenotypic definition of Chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15. American Journal of Medical Genetics Part A 140: 2776-2785.
Brown PD, Davies SL, Speake T, Millar ID (2004). Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129: 957-970.
Buell TJ, Heiss JD, Oldfield EH (2015). Pathogenesis and cerebrospinal fluid hydrodynamics of the Chiari I malformation. Neurosurgery Clinics of North America 26: 495-499.
Chang J, Baloh RH, Milbrandt J (2009). The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons. Journal of Cell Science 122: 2274-2282.
Chen JQ, Papp G, Póliska S, Szabó K, Tarr T et al. (2017). MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjögren’s syndrome. PLoS One 12: e0174585.
Del Toro D, Ruff T, Cederfjäll E, Villalba A, Seyit-Bremer G et al. (2017). Regulation of cerebral cortex folding by controlling neuronal migration via FLRT adhesion molecules. Cell 169: 621-635.e616.
Edilova MI, Abdul-Sater AA, Watts TH (2018). TRAF1 signaling in human health and disease. Frontiers in Immunology 9: 2969- 2969.
Furutani Y, Manabe R-I, Tsutsui K, Yamada T, Sugimoto N et al. (2005). Identification and characterization of photomedins: novel olfactomedin-domain-containing proteins with chondroitin sulphate-E-binding activity. Biochemical Journal 389: 675-684.
Gaudet P, Livstone MS, Lewis SE, Thomas PD (2011). Phylogeneticbased propagation of functional annotations within the Gene Ontology consortium. Briefings in Bioinformatics 12: 449-462.
Gong SG, Mai S, Chung K, Wei K (2009). Flrt2 and Flrt3 have overlapping and non-overlapping expression during craniofacial development. Gene Expression Patterns 9: 497- 502.
Gould DB, Phalan FC, Van Mil SE, Sundberg JP, Vahedi K et al. (2006). Role of COL4A1 in small-vessel disease and hemorrhagic stroke. New England Journal of Medicine 354: 1489-1496.
Hong EP, Kim BJ, Cho SS, Yang JS, Choi HJ et al. (2019). Genomic variations in susceptibility to intracranial aneurysm in the Korean population. Journal of Clinical Medicine 8: 275.
Huang S-C, Hua D-J, Sun Q-Q, Zhang L-N, Cen H et al. (2019). Associations of TRAF1/C5 rs10818488 and rs3761847 polymorphisms with genetic susceptibility to rheumatoid arthritis: a case-control study and updated meta-analysis. Central European Journal of Immunology 44: 159-173.
Keser N, Kuskucu A, Is M, Celikoglu E (2019). Familial Chiari type 1: a molecular karyotyping study in a Turkish family and review of the literature. World Neurosurgery 121: e852-e857.
Khoshnoodi J, Pedchenko V, Hudson BG (2008). Mammalian collagen IV. Microscopy Research and Technique 71: 357-370.
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C et al. (2018). ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Research 46: D1062-D1067.
Langridge B, Phillips E, Choi D (2017). Chiari malformation type 1: a systematic review of natural history and conservative management. World Neurosurgery 104: 213-219.
Lu YC, Nazarko OV, Sando III R, Salzman GS, Li N-S et al. (2015). Structural basis of latrophilin-FLRT-UNC5 interaction in cell adhesion. Structure 23: 1678-1691.
Markunas CA, Soldano K, Dunlap K, Cope H, Asiimwe E et al. (2013). Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. PLoS One 8: e61521.
Meadows J, Kraut M, Guarnieri M, Haroun RI, Carson BS (2000). Asymptomatic Chiari type I malformations identified on magnetic resonance imaging. Journal of Neurosurgery 92: 920- 926.
Merello E, Tattini L, Magi A, Accogli A, Piatelli G et al. (2017). Exome sequencing of two Italian pedigrees with non-isolated Chiari malformation type I reveals candidate genes for craniofacial development. European Journal of Human Genetics 25: 952-959.
Nagy L, Mobley J, Ray C (2016). Familial aggregation of Chiari malformation: presentation, pedigree, and review of the literature. Turkish Neurosurgery 26: 315-320.
Ortolani F, Tummolo A, Fedele S, Masciopinto M, Pesce S et al. (2014). Autoimmune disease and Arnold Chiari syndrome: any correlation? Hormone Research in Paediatrics 82.
Pasternak JF, Mantovani JF, Volpe JJ (1980). Porencephaly from periventricular intracerebral hemorrhage in a premature infant. The American Journal of Diseases Children 134: 673- 675.
Peña-Münzenmayer G, George AT, Shull GE, Melvin JE, Catalán MA (2016). Ae4 (Slc4a9) is an electroneutral monovalent cation-dependent Cl−/HCO3− exchanger. Journal of General Physiology 147: 423-436.
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF et al. (2007). TRAF1–C5 as a risk locus for rheumatoid arthritis — a genomewide study. New England Journal of Medicine 357: 1199-1209.
Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A et al. (2010). Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 466: 503-507.
Schijman E (2004). History, anatomic forms, and pathogenesis of Chiari I malformations. Child’s Nervous System 20: 323-328.
Shah A, Dhar A, Elsanafiry M, Goel A (2017). Chiari malformation: has the dilemma ended? Journal of Craniovertebral Junction and Spine 8: 297-304.
Sistani L, Rodriguez PQ, Hultenby K, Uhlen M, Betsholtz C et al. (2013). Neuronal proteins are novel components of podocyte major processes and their expression in glomerular crescents supports their role in crescent formation. Kidney International 83: 63-71.
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D et al. (2015). STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Research 43: D447-D452.
Tsukada Y-i, Ishitani T, Nakayama KI (2010). KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development. Genes and Development 24: 432-437.
Urbizu A, Toma C, Poca MA, Sahuquillo J, Cuenca-León E et al. (2013). Chiari malformation type I: a case-control association study of 58 developmental genes. PLoS One 8: e57241.
Van der Knaap MS, Smit LM, Barkhof F, Pijnenburg YA, Zweegman S et al. (2006). Neonatal porencephaly and adult stroke related to mutations in collagen IV A1. Annals of Neurology 59: 504- 511.
Wang Y, Sha N, Fang Y (2009). Analysis of genome-wide association data by large-scale Bayesian logistic regression. BMC Proceedings 3 Supplement 7: S16.
Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M et al. (2012). A genome-wide association study of attempted suicide. Molecular Psychiatry 17: 433-444.
Wilson PM, Fryer RH, Fang Y, Hatten ME (2010). Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. Journal of Neuroscience 30: 8529-8540.
Yaramis A, Lochmüller H, Töpf A, Sonmezler E, Yilmaz E et al. (2020). COL4A1- related autosomal recessive encephalopathy in 2 Turkish children. Neurology Genetics 6: e392.
Zhao JL, Li MH, Wang CL, Meng W (2016). A systematic review of Chiari I malformation: techniques and outcomes. World Neurosurgery 88: 7-14.