Chiari type 1 malformation (CMI) is a congenital anomaly characterized by the herniation of the tonsils of the cerebellum into the top of the spinal column. CMI could affect as many as 1 in 1280 people and includes varied symptoms such as severe headaches, sensory disruptions, and cardiac abnormalities. It is estimated that 65-80% of CMI patients develop syringomyelia, a fluid filled cyst in the spinal cord that can lead to nerve damage including loss of motor control. Because Chiari type I malformation is only diagnosed by magnetic resonance imaging (MRI), research into its etiology is only beginning;thus, given its frequency, this condition is vastly understudied. Highly invasive surgery is the only treatment for CMI with only 40-60% of treated patients showing improvement in their symptoms. Familial aggregation studies, including concordant twins, and cosegregating genetic conditions support a genetic component to CMI etiology. Currently, the predominant theory for etiology is a "too small posterior fossa," but the genetic component behind this theory is unclear. Identifying an underlying gene and/or genes will aide identification of high-risk individuals for earlier interventions, and this work will support the development of targeted therapeutics to treat the chronic, often intractable, pain associated with this condition. Through a variety of preliminary studies, we have established that there is an underlying genetic basis for at least a subset of non-syndromic Chiari type I malformations. Furthermore, an initial genomic screen on a relatively small group of families demonstrated two primary regions of interest. Based on these findings, we propose to continue investigating the hypothesis that some non-syndromic Chiari type I malformation families have an underlying genetic basis that can be identified through genetic analysis. The hypothesis will be tested and expanded by performing a high density whole genome association screen on our CMI family cohort to confirm and further narrow previous regions of genomic region(s) of interest, fine mapping to identify the minimum candidate interval, and testing candidate genes for evidence of disease-associated variation.

Public Health Relevance

Chiari type 1 malformation (CMI) is a developmental anomaly characterized by the herniation of a region of the brain into the top of the spinal column and could affect as many as 1 in 1280 people. Symptoms of CMI include severe headaches, sensory disruptions, and cardiac abnormalities. We have established that there is an underlying genetic basis for non-syndromic CMI. To identify the genes underlying this disease we propose to 1) perform a whole genome association screen on our CMI families, 2) confirm and further narrow previous regions of genomic region(s) of interest, and 3) test candidate genes for evidence of disease-associated variation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063273-05
Application #
8496141
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Riddle, Robert D
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$340,905
Indirect Cost
$122,376
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Markunas, Christina A; Lock, Eric; Soldano, Karen et al. (2014) Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics. BMC Med Genomics 7:39
Markunas, Christina A; Enterline, David S; Dunlap, Kaitlyn et al. (2014) Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation. Ann Hum Genet 78:1-12
Markunas, Christina A; Soldano, Karen; Dunlap, Kaitlyn 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
Markunas, Christina A; Tubbs, R Shane; Moftakhar, Roham et al. (2012) Clinical, radiological, and genetic similarities between patients with Chiari Type I and Type 0 malformations. J Neurosurg Pediatr 9:372-8