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Chiari Malformation Type I : a Case-Control Association Study of 58 Developmental Genes
Urbizu, Aintzane (Vall d'Hebron Hospitals. Institut de Recerca)
Toma, Claudio (Universitat de Barcelona. Departament de Genètica)
Poca Pastor, María Antonia (Vall d'Hebron Hospitals. Institut de Recerca)
Sahuquillo Barris, Juan (Vall d'Hebron Hospitals. Institut de Recerca)
Cuenca León, Ester (Vall d'Hebron Hospitals. Institut de Recerca)
Cormand Rifà, Bru (Universitat de Barcelona. Departament de Genètica)
Macaya Ruiz, Alfons (Vall d'Hebron Hospitals. Institut de Recerca)

Date: 2013
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.
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Subject: Morphometry ; Magnetic resonance imaging ; Mesoderm ; Genotyping ; Haplotypes ; Variant genotypes ; Somites ; Syringomyelia and syringobulbia
Published in: PloS one, Vol. 8 Issue 2 (February 2013) , p. e57241, ISSN 1932-6203

DOI: 10.1371/journal.pone.0057241
PMID: 23437350

10 p, 379.3 KB

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Articles > Research articles
Articles > Published articles

 Record created 2015-10-20, last modified 2019-11-07

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