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



Chiari 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.


A 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.


All 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.


Our 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.





Published Version (Please cite this version)


Publication Info

Markunas, Christina A, Eric Lock, Karen Soldano, Heidi Cope, Chien-Kuang C Ding, David S Enterline, Gerald Grant, Herbert Fuchs, et al. (2014). Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics. BMC medical genomics, 7(1). p. 39. 10.1186/1755-8794-7-39 Retrieved from

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David Scott Enterline

Consulting Associate in the Department of Radiology

Neuroradiology and Interventional Neuroradiology

Modalities Improvements: MRI, MDCT, CT Angiography, Angiography
Adult Neuroradiology -
Vascular Diseases, Brain Tumors, Spine Disease,
Pediatric Neuroradiology -
Brain Tumors, Congenital & Genetic Diseases, Chiari I malformation, Seizure Disorders
Interventional Neuroradiology -
Carotid Stents, Endovascular treatment of cerebral aneurysms and
AVMs, Vertebroplasty & Kyphoplasty, Spine Pain Management


Gerald Arthur Grant

Allan H. Friedman Distinguished Professor of Neurosurgery

Herbert Edgar Fuchs

Professor of Neurosurgery

Clinical neuro-oncology research including collaborations studying molecular genetics of childhood brain tumors.
Potential role of the free electron laser in surgery of pediatric brain tumors. Current work includes animal models with human brain tumor xenografts in preclinical studies.
Collaboration with the neurooncology laboratory of Dr. Darell Bigner in preclinical studies of new therapeutic agents.


Allison Elizabeth Ashley-Koch

Professor in Medicine

One of my major research foci is in the genetic basis of psychiatric and neurological disorders. I am currently involved in studies to dissect the genetic etiology of attention deficit hyperactivity disorder (ADHD), autism, chiari type I malformations, essential tremor, and neural tube defects. Additional research foci include genetic modifiers of sickle cell disease, and genetic contributions to birth outcomes, particularly among African American women.

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