Chiari malformation type I: a case-control association study of 58 developmental genes

Abstract

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.

Figure 1. Typical neuroradiological findings in CMI.

A) T1-weighted mid-sagittal MR image showing downward herniation of the cerebellar tonsils (a) and hypoplasia of the occipital components of the posterior cranial fossa (b): the supraocciput (c) and the basiocciput (d). B) Morphological measurements performed: length of tonsillar descent (f), supraocciput (g-b) and clivus (c–d) and foramen magnum diameter (b–c). The antero-posterior diameter of PCF (h) was inferred from a line running from the internal occipital protuberance (a) to top of the dorsum sellae (d). The PCF area was estimated as the polygon delimited by (a) (b) (c) (d) and (e) and the osseus PCF area as the one delimited by (a) (b) (c) and (d). Angular measurements: tentorium angle (i), basal angulation (j) and Wackenheim angle (k).

Figure 2. Quantile-quantile plot of the 303 P-values obtained in the association study under the additive model.

404 CMI patients versus 519 controls (A), and 186 small-PCF CMI versus 519 controls (B). SNPs with P-value<0.01 are indicated. Asterisks denote SNPs displaying association after 10% FDR correction for multiple testing (P<2.09E-03).

Figure 3. Haploview graphs showing the markers tested and haplotype blocks constructed for ALDH1A2, CDX1 and FLT1.

D′ values are indicated (tones from white to dark grey indicate D′ values from 0 to 1, respectively). The genomic structures of ALDH1A2, CDX1 and FLT1 genes are drawn with coding exons indicated as black boxes. The SNPs with P-value<0.01 are indicated with an asterisk (*); the SNPs showing association after 10% FDR correction for multiple testing (P<2.09E-03) are indicated with a double asterisk (**).