Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics

Abstract

BackgroundChiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.MethodsA collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.ResultsAll clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.ConclusionsOur results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.

Morphogenesis of Canine Chiari Malformation and Secondary Syringomyelia: Disorders of Cerebrospinal Fluid Circulation

“…For example, a familial group of Griffon Bruxellois, with a rounded cerebellum (CM0), had ventriculomegaly, heighted cranial fossa and SM indicating disruption of CSF flow ( 29 ). Similarly, the description of Chiari malformation in humans has morphed over time and includes CM Type 0 with normally placed cerebellar tonsils ( 21 , 30 ). The human classification of SM has also changed over time ( 25 , 31 ) with advanced imaging techniques applied to CSF circulation and it is possible that further phenotypic variations for both SM and CM may be revealed.…”

Population-based description of familial clustering of Chiari malformation Type I

“…In a set of 2 publications, Markunas et al 9,10 examined the relationship between cranial base morphometrics and whole-genome expression profiles, finding that much posterior fossa morphology was heritable. Multiple genomic regions were strongly implicated with posterior fossa morphology using ordered subset analysis, including chromosomes 1 and 22.…”

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

“…Genome-wide association studies have identified genes involved in chondrogenesis, such as EP3000 , CREBBP , SOX9 , ATF4 and LHX4. 45 A limited number of case reports have presented the association of this condition with abnormal skull morphology, especially due to a small posterior fossa in the context of bone disorders such as X-linked recessive hypophosphatemic rickets (OMIM #300554), or its X-linked dominant counterpart (OMIM # 307800). 46,47 However, a clear mechanistic association between these conditions has not been accomplished.…”