Is the Chiari I Malformation genetic? Part 2

Diane Mueller, ND, RN, FNP-BC

In part I of this review, 7 case reports of familial CMI was presented. However, many more cases were found in the English literature. In light of the seeming preponderance of familial CMI, one might conclude that there is an underlying mechanism at work related to the occurrence of CMI.  For many years, researchers have hypothesized that there is a genetic factor in the development of CMI.

In 2003, Speer, et al. hypothesized a genetic component for CMI. In this report, evidence was presented to support familial aggregation among first-degree relatives of persons with known CMI.  Thirty one family members in which 2 or more individuals were diagnosed with CMI were studied. There was some evidence to support parent-to-child (mother-child/father-child) of a CM trait, however no specific gene was isolated. Results of the study “demonstrated clear evidence of familial clustering of CMI/SM”.  The study went on to observe that most of the patients showed evidence of skull base bone abnormalities when compared to persons without CMI, which also suggested genetic component.

In 2003, Speer, et al published a review article which identified and discussed genetic syndromes that can be associated with some cases of CMI. The authors suggested evidence of a genetic component for a subset of persons with CMI. At the time of publication, research was ongoing for a genomic screen “to identify regions of the genome that may harbor susceptibility genes”.

Boyles, et al. (2006) reported research utilizing the DNA of 23 family members, with 71 affected by CMI. The authors performed screens on genomes in attempt to identify gene linkages to CMI. The researchers also measured the posterior fossa size/volume in the affected individuals in attempt to determine evidence of hereditarily abnormal dimensions. Results of the DNA samples indicated a positive linkage on chromosomes 9 and 15- indicating a possible genetic role in CMI.

In February 2013, Urbizu, et al reported research studying 303 single nucleotide polymorphisms (SNP) using 58 candidate genes.  The study participants consisted of 415 patients with symptomatic CMI, matched with control samples from 524 healthy blood donors. Only 6% of the CMI patients had a first degree relative with a known diagnosis of CMI. The authors concluded that “genetic data give support to the hypothesis that variants in genes involved in paraxial mesoderm may determine PCF size to the extent of the development of the CMI”.

More recently, Markunas, et al (2013) presented genome linkage using 367 self-referred participants from 66 CMI families. The participants were enrolled in the study if at least 2 persons within the family were diagnosed with CMI. Serum samples were collected from the CMI member and their immediate family members for DNA analysis. The authors concluded that “analysis resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity”.

Although much research is ongoing to determine a genetic basis for CMI, to date no specific gene has been identified. From the abundance of familial CMI case studies in the literature, one could hypothesize that there is a hereditary component to CMI.  However, there is no evidence to support that CMI occurs in every family.  It is important to remember that CMI is a multi-dimensional disorder that can encompass many factors. Only through continued research can we better understand this complex disorder.



One of the premier centers undertaking research on the genetic basis of CMI is Duke University -for more information, visit ).  Another ongoing genetic study is being performed by the National Institute of Health - for more information, visit

Speer, M.C., George, T.M., Enterline, D.S., Franklin, A., Wolpert, C.M., Milhorat, T.H. A genetic hypothesis for Chiari I malformation with or without syringomyelia. Neurosurg Focus; 8(3) Article 12, 2000.

Speer M.C., Enterline D.S., Mehltretter L., Hammock P., Joseph J., Dickerson M., Ellenbogen R.G., Milhorat T.H., Hauser M.A., George T.M. Review article: Chiari type I malformation with or without syringomyelia: prevalence and genetics. Journal of Genetic Counseling.  2003: 12(4), 297-311.

Boyles AL, Enterline DS, Hammock PH, Siegel DG, Slifer SH, Mehltretter L, Gilbert JR, Hu-Lince D, Stephan D, Batzdorf U, Benzel E, Ellenbogen R, Green BA, Kula R, Menezes A, Mueller D, Oro' JJ, Iskandar BJ, George TM, Milhorat TH, Speer MC. 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. Am J Med Genet Part A 140A:2776–2785.

Urbizu A., Toma C., Poca M.A., Sahuquillo J., Cuenca-Leon,E., COmand B., & Macaya A. Chiari malformation type I: A case-control association study of 58 developmental genes. PLoS One. 2013;8(2):e57241. doi: 10.1371/journal.pone.0057241. Epub 2013 Feb 21.

Markunas C.A., Soldano K., Dunlap K., Cope H., Asiimwe E., Stajich J., Enterline D., Grant G., Fuchs H., Gregory S. G., & Ashley-Koch A. E. Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil Syndrome genes as putative disease candidates. PLoS One. 2013:8(4):e61521.