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Title: Genetic variation in the non-canonical Wnt signalling pathway and predisposition to tetralogy of Fallot
Author: Palomino Doza, Addison Julian
ISNI:       0000 0004 2711 047X
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Introduction Congenital cardiovascular malformation (CCM) is a prevalent group of conditions in humans. Tetralogy of Fallot (TOF) is the commonest cyanotic heart defect affecting 0.24/1000 newborns worldwide. Human CCM etiology has a genetic component with 17% of CCM attributable to particular genetic syndromes. The remaining 80% of "sporadic" cases nevertheless show a high heritability, suggesting complex polygenic inheritance modulated by environmental factors. Multiple previous studies have explored the involvement of the non-canonical Wnt signaling pathway, also known as the planar cell polarity pathway, in cardiogenesis but none has explored the relationship between genetic variation within the pathway and predisposition to TOF in humans. Methods Exonic sequences of 7 key genes within the pathway (ROCK1, ROCK2, Wnt11, Wnt5a, Dvl3, Dvl1l1 and ANKRD6) were obtained in 93 TOF probands as an initial mutational screen. All novel variants were genotyped in at least 465 TOF probands and 1465 controls and analyzed using in silico methods to determine impact in structure and splicing. Three variants were functionally assessed. Genotypes for tag SNPs in ROCK1 were also obtained. Results Twelve uncommon previously unreported variants were found within the seven genes: four non synonymous, 3 synonymous, 3 intronic (near exon/intron boundaries) and 2 located at untranslated regions. Two novel common variants were also found: one synonymous and one intronic. None of the variants was proven to be de novo. None of the probands carried more than one novel variant. Statistically significant differences in allele frequencies were found for ROCK1 C807T and WNT11 207 +47 G>T. WNT5A Asp119Ser was found as a singleton in one proband and not in controls. Functional experiments did not show splicing changes associated with ROCK1 C807T and WNT11 207 +47 G>T. Rs288979, an intronic common variant (mAF=0.051) was significantly associated with TOF (p=0.000015 OR: 0.61). Conclusions Results of this work suggest that genetic variation in the non canonical Wnt signaling genes is involved in the etiology of TOF in humans. The genetic predisposition to TOF seems to be given by a combination of rare variants (ROCK1 C807T, WNT11 207 +47 G>T and WNT5A Asp119Ser) associated with high ORs and common variants (rs288979) associated with low ORs. Further deep sequencing work in larger samples should unravel the remaining rare variants associated with TOF, while genome-wide association study (GWAS) may reveal the role for additional common variants.
Supervisor: Not available Sponsor: Newcastle University ; Faculty of Medicine, Universidad de los Andes, Colombia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available