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

Data:	2013
Resum:	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.
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Morphometry ; Magnetic resonance imaging ; Mesoderm ; Genotyping ; Haplotypes ; Variant genotypes ; Somites ; Syringomyelia and syringobulbia
Publicat a:	PloS one, Vol. 8 Issue 2 (February 2013) , p. e57241, ISSN 1932-6203

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

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