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.


Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aldehyde Dehydrogenase 1 Family
  • Arnold-Chiari Malformation / genetics*
  • Arnold-Chiari Malformation / metabolism
  • Arnold-Chiari Malformation / pathology
  • Case-Control Studies
  • Cranial Fossa, Posterior / abnormalities
  • Cranial Fossa, Posterior / growth & development
  • Cranial Fossa, Posterior / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Genes, Developmental*
  • Genome-Wide Association Study
  • Haplotypes
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Morphogenesis / genetics*
  • Polymorphism, Single Nucleotide
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Rhombencephalon / abnormalities
  • Rhombencephalon / growth & development
  • Rhombencephalon / metabolism*
  • Risk
  • Somites / abnormalities
  • Somites / growth & development
  • Somites / metabolism*


  • CDX1 protein, human
  • Homeodomain Proteins
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A2 protein, human
  • Retinal Dehydrogenase

Grants and funding

Work supported by Instituto de Salud Carlos III, Spain,grant PI061606; Fundació La Marató TV3, Spain, grant 062710; and Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Spain, grant 2009SGR -0078. A.U. is the recipient of a scholarship from AGAUR (Spain). C.T. was supported by the European Union (Marie Curie, PIEF-GA-2009-254930). Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.