Dataset Information

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 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.

SUBMITTER: AvSar T

PROVIDER: S-EPMC7759189 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

AvŞar Timuçin T ÇaliŞ Şeyma Ş Yilmaz Baran B Demİrcİ OtluoĞlu Gülden G Holyavkİn Can C KiliÇ Türker T

Turkish journal of biology = Turk biyoloji dergisi 20201214 6

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 genom ...[more]

PMID: 33402871

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Project description:BackgroundSyringomyelia (SM) is a common condition affecting brachycephalic toy breed dogs and is characterized by the development of fluid-filled cavities within the spinal cord. It is often concurrent with a complex developmental malformation of the skull and craniocervical vertebrae called Chiari-like malformation (CM) characterized by a conformational change and overcrowding of the brain and cervical spinal cord particularly at the craniocervical junction. CM and SM have a polygenic mode of inheritance with variable penetrance.ResultsWe identified six cranial T1-weighted sagittal MRI measurements that were associated to maximum transverse diameter of the syrinx cavity. Increased syrinx transverse diameter has been correlated previously with increased likelihood of behavioral signs of pain. We next conducted a whole genome association study of these traits in 65 Cavalier King Charles Spaniel (CKCS) dogs (33 controls, 32 with extreme phenotypes). Two loci on CFA22 and CFA26 were found to be significantly associated to two traits associated with a reduced volume and altered orientation of the caudal cranial fossa. Their reconstructed haplotypes defined two associated regions that harbor only two genes: PCDH17 on CFA22 and ZWINT on CFA26. PCDH17 codes for a cell adhesion molecule expressed specifically in the brain and spinal cord. ZWINT plays a role in chromosome segregation and its expression is increased with the onset of neuropathic pain. Targeted genomic sequencing of these regions identified respectively 37 and 339 SNPs with significantly associated P values. Genotyping of tagSNPs selected from these 2 candidate loci in an extended cohort of 461 CKCS (187 unaffected, 274 SM affected) identified 2 SNPs on CFA22 that were significantly associated to SM strengthening the candidacy of this locus in SM development.ConclusionsWe identified 2 loci on CFA22 and CFA26 that contained only 2 genes, PCDH17 and ZWINT, significantly associated to two traits associated with syrinx transverse diameter. The locus on CFA22 was significantly associated to SM secondary to CM in the CKCS dog breed strengthening its candidacy for this disease. This study will provide an entry point for identification of the genetic factors predisposing to this condition and its underlying pathogenic mechanisms.

Project description:Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Project description:OBJECT:Chiari malformation Type I (CM-I) is characterized by hindbrain deformity. We investigated the effects of craniocervical decompression surgery on the anatomical features of hindbrain deformity with a prospective MRI study of patients with CM-I. METHODS:A prospective longitudinal study was conducted in 48 patients with CM-I (39 with syringomyelia) treated with craniocervical decompression. Clinical examinations and cervical MRI were performed before surgery and 1 week, 3-6 months, and annually after surgery. Hindbrain deformity was defined by tonsillar ectopia, pointed cerebellar tonsils, and/or cervicomedullary protuberance. The length of the clivus, basiocciput (sphenooccipital synchondrosis to basion), supraocciput (internal occipital protuberance to opisthion), and anteroposterior (AP) width of CSF pathways at the foramen magnum were measured and compared with those from 18 healthy volunteers (control group). RESULTS:Before surgery, the patients' posterior fossa bones were short and their CSF pathways were narrow. All patients had tonsillar ectopia (mean [± SD] 12.3 ± 5.1 mm; normal 0.3 ± 1.0). The majority of patients had pointed tonsils and more than two-thirds exhibited a cervicomedullary protuberance. Clivus and basiocciput lengths were significantly shorter than the values obtained in the control group. However, the supraocciput length did not differ significantly from control measurements. The mean bulbopontine sulcus distance superior to the basion was 9.5 ± 2.6 mm (vs 13.6 ± 2.8 mm in controls; p < 0.0001). The AP widths of the CSF pathways at the level of the foramen magnum were significantly narrowed. After surgery, CSF pathways significantly expanded both ventrally and dorsally. By 3-6 months after surgery, pointed tonsils became round, cervicomedullary protuberance disappeared, and tonsillar ectopia diminished by 51% (to 6.0 ± 3.3 mm; p < 0.0001). CONCLUSIONS:The cerebellar tonsils and brainstem assumed a normal appearance within 6 months after craniocervical decompression. These findings support the concept that the CM-I is not a congenital malformation of the neural elements but rather an acquired malformation that arises from pulsatile impaction of the cerebellar tonsils into the foramen magnum. Clinical trial registration no.: NCT00001327.

Dataset Information

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

Publications

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

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